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Structural Variability and Flexibility of the Genome

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 33899

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Special Issue Editor

Dr. Thomas Liehr

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Institute of Human Genetics, Jena University Hospital, Jena, Germany
Interests: chromosome biology; chromosomal rearrangements; small supernumerary marker chromosomes; heteromorphisms; molecular cytogenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genomes of eukaryotes are known in more and more detail due to DNA-directed studies at different levels of resolution. Already with the help of cytogenetics, first insights into structural genomic variants, like chromosomal heteromorphims, can be obtained. Underlying copy number variants can be further elucidated by means of molecular cytogenetics, molecular karyotyping, and/or sequencing approaches. Further, epigenetics may play a role for both structural as well as flexible adaptations of genomes under specific evolutionary pressures. In the thus far best studied eukaryotic genome, the human one, copy number variants as well a three-dimensional networking of the genome in ‘topologically associated domains’ (= TADs) are recognized to be important. Even when it comes to the origin of genetic disorders, underlying point mutations are not so much the only reason to be considered anymore.

For this Special Issue, we look forward to receiving original research manuscripts as well as methodological and review articles, with a special focus on structural variability and flexibility of the genome, which can be observable on variant levels (e.g., copy number variants of heterochromatic and euchromatic material, mechanisms of genetic silencing, position effects, 3D structure of the nucleus, epigenetic mechanisms). We are confident that different aspects of eukaryote genome complexity in one volume will provide an important contribution to molecular genetics and genomics.

Dr. Thomas Liehr
Guest Editor

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Keywords

copy number variants
gene silencing
position effects
topologically associated domains (TADs)
epigenetics
fragile sites
chromosomal evolution
repetitive elements
chromosomal rearrangements

Published Papers (12 papers)

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17 pages, 6388 KiB

Open AccessArticle

Cytogenomics Unveil Possible Transposable Elements Driving Rearrangements in Chromosomes 2 and 4 of Solea senegalensis

by María Esther Rodríguez, Ismael Cross, Alberto Arias-Pérez, Silvia Portela-Bens, Manuel Alejandro Merlo, Thomas Liehr and Laureana Rebordinos

Int. J. Mol. Sci. 2021, 22(4), 1614; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041614 - 05 Feb 2021

Cited by 3 | Viewed by 1714

Abstract

Cytogenomics, the integration of cytogenetic and genomic data, has been used here to reconstruct the evolution of chromosomes 2 and 4 of Solea senegalensis. S. senegalensis is a flat fish with a karyotype comprising 2n = 42 chromosomes: 6 metacentric + 4 submetacentric + 8 subtelocentric + 24 telocentric. The Fluorescence in situ Hybridization with Bacterial Artificial Chromosomes (FISH-BAC) technique was applied to locate BACs in these chromosomes (11 and 10 BACs in chromosomes 2 and 4, respectively) and to generate integrated maps. Synteny analysis, taking eight reference fish species (Cynoglossus semilaevis, Scophthalmus maximus, Sparus aurata, Gasterosteus aculeatus, Xiphophorus maculatus, Oryzias latipes, Danio rerio, and Lepisosteus oculatus) for comparison, showed that the BACs of these two chromosomes of S. senegalensis were mainly distributed in two principal chromosomes in the reference species. Transposable Elements (TE) analysis showed significant differences between the two chromosomes, in terms of number of loci per Mb and coverage, and the class of TE (I or II) present. Analysis of TE divergence in chromosomes 2 and 4 compared to their syntenic regions in four reference fish species (C. semilaevis, S. maximus, O. latipes, and D. rerio) revealed differences in their age of activity compared with those species but less notable differences between the two chromosomes. Differences were also observed in peaks of divergence and coverage of TE families for all reference species even in those close to S. senegalensis, like S. maximus and C. semilaevis. Considered together, chromosomes 2 and 4 have evolved by Robertsonian fusions, pericentric inversions, and other chromosomal rearrangements mediated by TEs. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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25 pages, 6150 KiB

Open AccessArticle

Evolution of MicroRNA Biogenesis Genes in the Sterlet (Acipenser ruthenus) and Other Polyploid Vertebrates

by Mikhail V. Fofanov, Dmitry Yu. Prokopov, Heiner Kuhl, Manfred Schartl and Vladimir A. Trifonov

Int. J. Mol. Sci. 2020, 21(24), 9562; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249562 - 15 Dec 2020

Cited by 2 | Viewed by 2213

Abstract

MicroRNAs play a crucial role in eukaryotic gene regulation. For a long time, only little was known about microRNA-based gene regulatory mechanisms in polyploid animal genomes due to difficulties of polyploid genome assembly. However, in recent years, several polyploid genomes of fish, amphibian, and even invertebrate species have been sequenced and assembled. Here we investigated several key microRNA-associated genes in the recently sequenced sterlet (Acipenser ruthenus) genome, whose lineage has undergone a whole genome duplication around 180 MYA. We show that two paralogs of drosha, dgcr8, xpo1, and xpo5 as well as most ago genes have been retained after the acipenserid-specific whole genome duplication, while ago1 and ago3 genes have lost one paralog. While most diploid vertebrates possess only a single copy of dicer1, we strikingly found four paralogs of this gene in the sterlet genome, derived from a tandem segmental duplication that occurred prior to the last whole genome duplication. ago1,3,4 and exportins1,5 look to be prone to additional segment duplications producing up to four-five paralog copies in ray-finned fishes. We demonstrate for the first time exon microsatellite amplification in the acipenserid drosha2 gene, resulting in a highly variable protein product, which may indicate sub- or neofunctionalization. Paralogous copies of most microRNA metabolism genes exhibit different expression profiles in various tissues and remain functional despite the rediploidization process. Subfunctionalization of microRNA processing gene paralogs may be beneficial for different pathways of microRNA metabolism. Genetic variability of microRNA processing genes may represent a substrate for natural selection, and, by increasing genetic plasticity, could facilitate adaptations to changing environments. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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16 pages, 2918 KiB

Open AccessArticle

by Roman O. Cherezov, Julia E. Vorontsova and Olga B. Simonova

Int. J. Mol. Sci. 2020, 21(22), 8871; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228871 - 23 Nov 2020

Cited by 2 | Viewed by 2555

Abstract

Robertsonian (centric-fusion) translocation is the form of chromosomal translocation in which two long arms of acrocentric chromosomes are fused to form one metacentric. These translocations reduce the number of chromosomes while preserving existing genes and are considered to contribute to speciation. We asked whether hypomorphic mutations in genes that disrupt the formation of pericentromeric regions could lead to centric fusion. TBP-related factor 2 (Trf2) encodes an alternative general transcription factor. A decrease of TRF2 expression disrupts the structure of the pericentromeric regions and prevents their association into chromocenter. We revealed several centric fusions in two lines of Drosophila melanogaster with weak Trf2 alleles in genetic experiments. We performed an RNAi-mediated knock-down of Trf2 in Drosophila and S2 cells and demonstrated that Trf2 upregulates expression of D1—one of the major genes responsible for chromocenter formation and nuclear integrity in Drosophila. Our data, for the first time, indicate that Trf2 may be involved in transcription program responsible for structuring of pericentromeric regions and may contribute to new karyotypes formation in particular by promoting centric fusion. Insight into the molecular mechanisms of Trf2 function and its new targets in different tissues will contribute to our understanding of its phenomenon. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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13 pages, 1375 KiB

Open AccessArticle

The Cytogenomic “Theory of Everything”: Chromohelkosis May Underlie Chromosomal Instability and Mosaicism in Disease and Aging

by Ivan Y. Iourov, Svetlana G. Vorsanova, Yuri B. Yurov, Maria A. Zelenova, Oxana S. Kurinnaia, Kirill S. Vasin and Sergei I. Kutsev

Int. J. Mol. Sci. 2020, 21(21), 8328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218328 - 06 Nov 2020

Cited by 19 | Viewed by 2488

Abstract

Mechanisms for somatic chromosomal mosaicism (SCM) and chromosomal instability (CIN) are not completely understood. During molecular karyotyping and bioinformatic analyses of children with neurodevelopmental disorders and congenital malformations (n = 612), we observed colocalization of regular chromosomal imbalances or copy number variations (CNV) with mosaic ones (n = 47 or 7.7%). Analyzing molecular karyotyping data and pathways affected by CNV burdens, we proposed a mechanism for SCM/CIN, which had been designated as “chromohelkosis” (from the Greek words chromosome ulceration/open wound). Briefly, structural chromosomal imbalances are likely to cause local instability (“wreckage”) at the breakpoints, which results either in partial/whole chromosome loss (e.g., aneuploidy) or elongation of duplicated regions. Accordingly, a function for classical/alpha satellite DNA (protection from the wreckage towards the centromere) has been hypothesized. Since SCM and CIN are ubiquitously involved in development, homeostasis and disease (e.g., prenatal development, cancer, brain diseases, aging), we have metaphorically (ironically) designate the system explaining chromohelkosis contribution to SCM/CIN as the cytogenomic “theory of everything”, similar to the homonymous theory in physics inasmuch as it might explain numerous phenomena in chromosome biology. Recognizing possible empirical and theoretical weaknesses of this “theory”, we nevertheless believe that studies of chromohelkosis-like processes are required to understand structural variability and flexibility of the genome. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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11 pages, 1058 KiB

Open AccessArticle

Doxorubicin-Induced Translocation of mtDNA into the Nuclear Genome of Human Lymphocytes Detected Using a Molecular-Cytogenetic Approach

by Tigran Harutyunyan, Ahmed Al-Rikabi, Anzhela Sargsyan, Galina Hovhannisyan, Rouben Aroutiounian and Thomas Liehr

Int. J. Mol. Sci. 2020, 21(20), 7690; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207690 - 17 Oct 2020

Cited by 5 | Viewed by 2028

Abstract

Translocation of mtDNA in the nuclear genome is an ongoing process that contributes to the development of pathological conditions in humans. However, the causal factors of this biological phenomenon in human cells are poorly studied. Here we analyzed mtDNA insertions in the nuclear genome of human lymphocytes after in vitro treatment with doxorubicin (DOX) using a fluorescence in situ hybridization (FISH) technique. The number of mtDNA insertions positively correlated with the number of DOX-induced micronuclei, suggesting that DOX-induced chromosome breaks contribute to insertion events. Analysis of the odds ratios (OR) revealed that DOX at concentrations of 0.025 and 0.035 µg/mL significantly increases the rate of mtDNA insertions (OR: 3.53 (95% CI: 1.42–8.76, p < 0.05) and 3.02 (95% CI: 1.19–7.62, p < 0.05), respectively). Analysis of the distribution of mtDNA insertions in the genome revealed that DOX-induced mtDNA insertions are more frequent in larger chromosomes, which are more prone to the damaging action of DOX. Overall, our data suggest that DOX-induced chromosome damage can be a causal factor for insertions of mtDNA in the nuclear genome of human lymphocytes. It can be assumed that the impact of a large number of external and internal mutagenic factors contributes significantly to the origin and amount of mtDNA in nuclear genomes. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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26 pages, 4402 KiB

Open AccessArticle

Meiotic Nuclear Architecture in Distinct Mole Vole Hybrids with Robertsonian Translocations: Chromosome Chains, Stretched Centromeres, and Distorted Recombination

by Sergey Matveevsky, Artemii Tretiakov, Anna Kashintsova, Irina Bakloushinskaya and Oxana Kolomiets

Int. J. Mol. Sci. 2020, 21(20), 7630; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207630 - 15 Oct 2020

Cited by 10 | Viewed by 2400

Abstract

Genome functioning in hybrids faces inconsistency. This mismatch is manifested clearly in meiosis during chromosome synapsis and recombination. Species with chromosomal variability can be a model for exploring genomic battles with high visibility due to the use of advanced immunocytochemical methods. We studied synaptonemal complexes (SC) and prophase I processes in 44-chromosome intraspecific (Ellobius tancrei × E. tancrei) and interspecific (Ellobius talpinus × E. tancrei) hybrid mole voles heterozygous for 10 Robertsonian translocations. The same pachytene failures were found for both types of hybrids. In the intraspecific hybrid, the chains were visible in the pachytene stage, then 10 closed SC trivalents formed in the late pachytene and diplotene stage. In the interspecific hybrid, as a rule, SC trivalents composed the SC chains and rarely could form closed configurations. Metacentrics involved with SC trivalents had stretched centromeres in interspecific hybrids. Linkage between neighboring SC trivalents was maintained by stretched centromeric regions of acrocentrics. This centromeric plasticity in structure and dynamics of SC trivalents was found for the first time. We assume that stretched centromeres were a marker of altered nuclear architecture in heterozygotes due to differences in the ancestral chromosomal territories of the parental species. Restructuring of the intranuclear organization and meiotic disturbances can contribute to the sterility of interspecific hybrids, and lead to the reproductive isolation of studied species. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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19 pages, 2373 KiB

Open AccessArticle

Small-Angle Scattering and Multifractal Analysis of DNA Sequences

by Eugen Mircea Anitas

Int. J. Mol. Sci. 2020, 21(13), 4651; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134651 - 30 Jun 2020

Cited by 8 | Viewed by 2065

Abstract

The arrangement of A, C, G and T nucleotides in large DNA sequences of many prokaryotic and eukaryotic cells exhibit long-range correlations with fractal properties. Chaos game representation (CGR) of such DNA sequences, followed by a multifractal analysis, is a useful way to analyze the corresponding scaling properties. This approach provides a powerful visualization method to characterize their spatial inhomogeneity, and allows discrimination between mono- and multifractal distributions. However, in some cases, two different arbitrary point distributions, may generate indistinguishable multifractal spectra. By using a new model based on multiplicative deterministic cascades, here it is shown that small-angle scattering (SAS) formalism can be used to address such issue, and to extract additional structural information. It is shown that the box-counting dimension given by multifractal spectra can be recovered from the scattering exponent of SAS intensity in the fractal region. This approach is illustrated for point distributions of CGR data corresponding to Escherichia coli, Phospholamban and Mouse mitochondrial DNA, and it is shown that for the latter two cases, SAS allows extraction of the fractal iteration number and the scaling factor corresponding to “ACGT” square, or to recover the number of bases. The results are compared with a model based on multiplicative deterministic cascades, and respectively with one which takes into account the existence of forbidden sequences in DNA. This allows a classification of the DNA sequences in terms of random and deterministic fractals structures emerging in CGR. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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12 pages, 1584 KiB

Open AccessArticle

Molecular Cytogenetic Analysis in Freshwater Prawns of the Genus Macrobrachium (Crustacea: Decapoda: Palaemonidae)

by Wagner F. Molina, Gideão W. W. F. Costa, Inailson M. C. Cunha, Luiz A. C. Bertollo, Tariq Ezaz, Thomas Liehr and Marcelo B. Cioffi

Int. J. Mol. Sci. 2020, 21(7), 2599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072599 - 09 Apr 2020

Cited by 9 | Viewed by 3461

Abstract

Freshwater prawns of the genus Macrobrachium are one of the important components of circumtropical marine, estuarine, and freshwater environments. They have been extensively exploited for human consumption for many years. More than 250 species reflect the evolutionary success of this highly diversified group, with a complex and challenging taxonomy due to morphological variations and vast geographical distribution. Although genetic approaches have been used to clarify phylogenetic and taxonomic aspects of Macrobrachium species, cytogenetic information is still very scarce and mostly focused on chromosome number and morphology. Here, we present chromosome data for three species from the Neotropical region, M. carcinus, M. acanthurus, and M. amazonicum, and one species from the Oriental region, M. rosenbergii. Using conventional cytogenetic approaches and chromosome mapping of repetitive DNAs by fluorescence in situ hybridization (FISH), we identified numerical diversification of the diploid set, within and between both zoogeographic regions. These included M. acanthurus and M. amazonicum sharing diploid chromosomes of 98, while M. carcinus has 94, and M. rosenbergii has 118 chromosomes. Argentophilic sites are also variable in number, but they occur in a much higher number than 18S rDNA, representing two to 10 sites within the study species. Microsatellites repeat motifs are also abundant in the chromosomes, with a co-localization and uniform distribution along the chromosome arms, but completely absent in the AT-rich centromeric regions. As a whole, our study suggests that the 2n divergence was followed by a considerable rDNA diversification. The abundance of the exceptional amount of microsatellite sequences in the chromosomes also suggests that they are essential components of the Macrobrachium genome and, therefore, maintained as a shared feature by the species, the reason for which is yet unknown. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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Review

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11 pages, 956 KiB

Open AccessReview

Lessons Learned from CNV Analysis of Major Birth Defects

by Alina Christine Hilger, Gabriel Clemens Dworschak and Heiko Martin Reutter

Int. J. Mol. Sci. 2020, 21(21), 8247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218247 - 03 Nov 2020

Cited by 8 | Viewed by 2195

Abstract

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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15 pages, 488 KiB

Open AccessReview

Insight into the Genome of Diverse Penicillium chrysogenum Strains: Specific Genes, Cluster Duplications and DNA Fragment Translocations

by Juan F. Martín

Int. J. Mol. Sci. 2020, 21(11), 3936; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113936 - 30 May 2020

Cited by 10 | Viewed by 3474

Abstract

Background: There are eighteen species within the Penicillium genus section chrysogena, including the original penicillin producers Penicillium notatum (Fleming strain) and Penicillium chrysogenum NRRL 1951. Other wild type isolates of the Penicillium genus are relevant for the production of useful proteins and primary or secondary metabolites. The aim of this article is to characterize strain specific genes and those genes which are involved in secondary metabolite biosynthesis, particularly the mutations that have been introduced during the β-lactams strain improvement programs. Results: The available genomes of several classical and novel P. chrysogenum strains have been compared. The first genome sequenced was that of the reference strain P. chrysogenum Wis54-1255, which derives from the wild type P. chrysogenum NRRL 1951; its genome size is 32.19 Mb and it encodes 12,943 proteins. Four chromosomes were resolved in P. chrysogenum and P. notatum by pulse field gel electrophoresis. The genomes of three industrial strains have a similar size but contain gene duplications and truncations; the penicillin gene cluster copy number ranges from one in the wild type to twelve in the P. chrysogenum ASP-E1 industrial strain and is organized in head to tail tandem repeats. The genomes of two new strains, P. chrysogenum KF-25, a producer of antifungal proteins isolated from a soil sample, and P. chrysogenum HKF2, a strain with carbohydrate-converting activities isolated from a sludge treatment plant, showed strain specific genes. Conclusions: The overall comparison of all available P. chrysogenum genomes indicates that there are a significant number of strain-specific genes, mutations of structural and regulatory genes, gene cluster duplications and DNA fragment translocations. This information provides important leads to improve the biosynthesis of enzymes, antifungal agents, prebiotics or different types of secondary metabolites. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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22 pages, 656 KiB

Open AccessReview

Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine

by Olga A. Efimova, Alla S. Koltsova, Mikhail I. Krapivin, Andrei V. Tikhonov and Anna A. Pendina

Int. J. Mol. Sci. 2020, 21(9), 3223; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093223 - 02 May 2020

Cited by 31 | Viewed by 6861

Abstract

Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulation and its flexibility. DNA methylation and demethylation is a key mechanism of genome programming and reprogramming. During ontogenesis, the DNA methylome undergoes both programmed changes and those induced by environmental and endogenous factors. The former enable accurate activation of developmental programs; the latter drive epigenetic responses to factors that directly or indirectly affect epigenetic biochemistry leading to alterations in genome regulation and mediating organism response to environmental transformations. Adverse environmental exposure can induce aberrant DNA methylation changes conducive to genetic dysfunction and, eventually, various pathologies. In recent years, evidence was derived that apart from 5-methylcytosine, the DNA methylation/demethylation cycle includes three other oxidative derivatives of cytosine—5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally induced adverse effects on 5hmC patterns in mammalian genomes. Types of environmental exposure under consideration include hypnotic drugs and medicines (i.e., phenobarbital, diethylstilbestrol, cocaine, methamphetamine, ethanol, dimethyl sulfoxide), as well as anthropogenic pollutants (i.e., heavy metals, particulate air pollution, bisphenol A, hydroquinone, and pentachlorophenol metabolites). We put a special focus on the discussion of molecular mechanisms underlying environmentally induced alterations in DNA hydroxymethylation patterns and their impact on genetic dysfunction. We conclude that DNA hydroxymethylation is a sensitive biosensor for many harmful environmental factors each of which specifically targets 5hmC in different organs, cell types, and DNA sequences and induces its changes through a specific metabolic pathway. The associated transcriptional changes suggest that environmentally induced 5hmC alterations play a role in epigenetically mediated genome flexibility. We believe that knowledge accumulated in this review together with further studies will provide a solid basis for new approaches to epigenetic therapy and chemoprevention of environmentally induced epigenetic toxicity involving 5hmC patterns. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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Other

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11 pages, 1055 KiB

Open AccessCase Report

Recombinant Chromosome 7 Driven by Maternal Chromosome 7 Pericentric Inversion in a Girl with Features of Silver-Russell Syndrome

by Ilaria Catusi, Maria Teresa Bonati, Ester Mainini, Silvia Russo, Eleonora Orlandini, Lidia Larizza and Maria Paola Recalcati

Int. J. Mol. Sci. 2020, 21(22), 8487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228487 - 11 Nov 2020

Cited by 1 | Viewed by 1692

Abstract

Maternal uniparental disomy of chromosome 7 is present in 5–10% of patients with Silver-Russell syndrome (SRS), and duplication of 7p including GRB10 (Growth Factor Receptor-Bound Protein 10), an imprinted gene that affects pre-and postnatal growth retardation, has been associated with the SRS phenotype. Here, we report on a 17 year old girl referred to array-CGH analysis for short stature, psychomotor delay, and relative macrocephaly. Array-CGH analysis showed two copy number variants (CNVs): a ~12.7 Mb gain in 7p13-p11.2, involving GRB10 and an ~9 Mb loss in 7q11.21-q11.23. FISH experiments performed on the proband’s mother showed a chromosome 7 pericentric inversion that might have mediated the complex rearrangement harbored by the daughter. Indeed, we found that segmental duplications, of which chromosome 7 is highly enriched, mapped at the breakpoints of both the mother’s inversion and the daughter’s CNVs. We postulate that pairing of highly homologous sequences might have perturbed the correct meiotic chromosome segregation, leading to unbalanced outcomes and acting as the putative meiotic mechanism that was causative of the proband’s rearrangement. Comparison of the girl’s phenotype to those of patients with similar CNVs supports the presence of 7p in a locus associated with features of SRS syndrome. Full article

(This article belongs to the Special Issue Structural Variability and Flexibility of the Genome)

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