Somatic Mosaicism

Se la secolarizzazione ha contribuito a desacralizzare numerosi spazi liturgici, al contrario la società globalizzata non ha mai cessato di cercare e di creare nuovi luoghi, in cui riconoscere e condividere forme di sacralità. Se dovessimo infatti individuare i luoghi oggi considerati scrigno di «sacralità», dovremmo indagare spazi con funzioni disparate, in cui i protagonisti non paiono più essere le singole persone, né tantomeno le comunità, quanto piuttosto alcune categorie di oggetti-simbolo che riportano ad archetipi del «sacro naturale», oramai sempre piu’ presenti nella società di massa, come ad esempio: i musei e le gallerie d’arte, gli allestimenti di mostre temporanee o gli show-room aziendali, le navate delle stazioni ferroviarie e degli aeroporti, alcuni
spazi pubblici urbani e quant’altro. «Se le religioni paiono aver talora rinunciato alla necessità di avere luoghi sacri, l’architettura pare invece non aver cessato di aver bisogno di sacro»
Nasce da queste riflessioni, l’idea e l’esigenza di andare a cercare una Basilica antica, come quella di Sant’Apollinare in Classe a Ravenna, che allontanandosi da sperimentazioni architettoniche tipologiche post-conciliari, a volte riuscite a volte no, ci permetta di poter individuare la presenza del «sacro naturale», che nel suo confluire nel «sacro cristiano» tramite gli splendidi spazi basilicali, ci possano far riflettere su
queste tematiche.
Tenteremo altresì di dimostrare in questo nostro breve elaborato, come lo spazio cristiano di questa antichissima basilica del VI secolo, abbia saputo sapientemente «rimescolare» gli elementi del «sacro naturale», nel sacro «cristiano», anche alla luce del recente e a mio avviso molto ben riuscito adeguamento liturgico, corrispondendo pienamente all’attuale sensibilità cristiana.

Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)-and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm Ϫ/Ϫ cerebral cortex and a dramatic 78% decrease in Trp53 Ϫ/Ϫ mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5 Ϫ/Ϫ mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5 Ϫ/Ϫ mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.

The extent to which normal (nonmalignant) cells of the body can evolve through mutation and selection during the lifetime of the organism has been a major unresolved issue in evolutionary and developmental studies. On the one hand, stable multicellular individuality seems to depend on genetic homogeneity and suppression of evolutionary conflicts at the cellular level. On the other hand, the example of clonal selection of lymphocytes indicates that certain forms of somatic mutation and selection are concordant with the organism-level fitness. Recent DNA sequencing and tissue physiology studies suggest that in addition to adaptive immune cells also neurons, epithelial cells, epidermal cells, hematopoietic stem cells and functional cells in solid bodily organs are subject to evolutionary forces during the lifetime of an organism. Here we refer to these recent studies and suggest that the expanding list of somatically evolving cells modifies idealized views of biological individuals as radically different from collectives.

Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.

A basic assumption about the normal nervous system is that its neurons possess identical genomes. Here we present direct evidence for genomic variability, manifested as chromosomal aneuploidy, among developing and mature neurons. Analysis of mouse embryonic cerebral cortical neuroblasts in situ detected lagging chromosomes during mitosis, suggesting the normal generation of aneuploidy in these somatic cells. Spectral karyotype analysis identified Ϸ33% of neuroblasts as aneuploid. Most cells lacked one chromosome, whereas others showed hyperploidy, monosomy, and͞or trisomy. The prevalence of aneuploidy was reduced by culturing cortical explants in medium containing fibroblast growth factor 2. Interphase fluorescence in situ hybridization on embryonic cortical cells supported the rate of aneuploidy observed by spectral karyotyping and detected aneuploidy in adult neurons. Our results demonstrate that genomes of developing and adult neurons can be different at the level of whole chromosomes.

This study aimed to investigate the effect of mannan-oligosaccharide (MOS) on the lipogram and selected organ functions in hyperlipidemic rats. Animals were subjected to different treatments for 60 days. Balanced basal diet was supplied to control rats; saturated high fat- and/or MOS-contained diets were supplied to tested rats. Sera were collected on escalating times and total lipids, cholesterol, triacylglycerols, HDL-C, LDL-C, VLDL-C, AST, ALT, urea and creatinine were evaluated. On the last day, rats were sacrificed and the kidneys, liver, heart with aorta were picked out for histopathology. The results of MOS-treated group revealed significant decrease in total lipids, cholesterol, LDL-C, VLDL-C, AST, ALT, urea and creatinine with significant increase in HDL-C. Histopathological findings in the tested organs have been ameliorated with MOS, comparing with those in hyperlipidemic rats. The obtained data may give MOS the potential of antihyperlipidemic activity for prophylaxis and treatment of hyperlipidemia and related diseases.

Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G > A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.

Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)-and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm Ϫ/Ϫ cerebral cortex and a dramatic 78% decrease in Trp53 Ϫ/Ϫ mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5 Ϫ/Ϫ mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5 Ϫ/Ϫ mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.

Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G > A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p....

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately...

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately...

LINE-1 (L1) elements are retrotransposons that insert extra copies of themselves throughout the genome using a "copy and paste" mechanism. L1s have contributed ~20% to total human genome content and are able to influence chromosome integrity and gene expression upon reinsertion. Recent studies show that L1 elements are active and "jumping" during neuronal differentiation. New somatic L1 insertions may generate "genomic plasticity" in neurons by causing variation in genomic DNA sequences and by altering the transcriptome of individual cells. Thus, L1-induced variation may affect neuronal plasticity and behavior. Here, we discuss potential consequences of L1-induced neuronal diversity and propose that a mechanism generating diversity in the brain could broaden the spectrum of behavioral phenotypes that can originate from any single genome.

Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)-and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm Ϫ/Ϫ cerebral cortex and a dramatic 78% decrease in Trp53 Ϫ/Ϫ mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5 Ϫ/Ϫ mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5 Ϫ/Ϫ mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.

Background: Although alpha-synuclein (SNCA) is crucial
to the pathogenesis of Parkinson’s disease (PD)
and dementia with Lewy bodies (DLB), mutations in
PROUKAKIS ET AL
1060 Movement Disorders, Vol. 29, No. 8, 2014
the gene appear to be rare. We have recently hypothesized
that somatic mutations in early development
could contribute to PD.
Methods: Expanding on our recent negative small
study, we used high-resolution melting (HRM) analysis
to screen SNCA coding exons for somatic point mutations
in DNA from 539 PD and DLB cerebellar samples,
with two additional regions (frontal cortex,
substantia nigra) for 20 PD cases. We used artificial
mosaics to determine sensitivity where possible.
Results: We did not detect any evidence of somatic
coding mutations. Three cases were heterozygous for
known silent polymorphisms. The protocol we used was
sensitive enough to detect 5% to 10% mutant DNA.
Conclusion: Using DNA predominantly from cerebellum,
but also from frontal cortex and substantia nigra
(n 5 20 each), we have not detected any somatic
coding SNCA point mutations. VC 2014 The Authors.
Movement Disorders published by Wiley Periodicals,
Inc. on behalf of International Parkinson and Movement
Disorder Society.
Key Words: SNCA; alpha-synuclein; somatic mutation;
mosaicism; etiology of Parkinson’s disease