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A Novelletto,
R Gulli,
P Ciotti,
C Vitale, P Malaspina,
P Blasi,
T Pippucci,
M Seri,
A Cozzolino,
L Bilo,
G Abbruzzese,
P Martinelli,
E Bellone,
P Barone,
P Mandich
European Journal of Neurology 09/2011; 18(9):e118-20. · 3.69 Impact Factor
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ABSTRACT: In mammals, increased GABA in the central nervous system has been associated with abnormalities of visual evoked potentials (VEPs), predominantly manifested as increased latency of the major positive component P100. Accordingly, we hypothesized that patients with a defect in GABA metabolism, succinate semialdehyde dehydrogenase (SSADH) deficiency (in whom supraphysiological levels of GABA accumulate), would manifest VEP anomalies. We evaluated VEPs on two patients with confirmed SSADH deficiency. Whereas the P100 latencies and amplitudes for binocular VEP analyses were within normal ranges for both patients, the P100 latencies were markedly delayed for left eye (OS) (and right eye (OD), patient 1) and monocular OS (patient 2): 134-147 ms; normal <118 ms. We hypothesize that elevated GABA in ocular tissue of SSADH patients leads to a use-dependent downregulation of the major GABAergic receptor in eye, GABA(C), and that the VEP recordings' abnormalities, as evidenced by P100 latency and/or amplitude measurements, may be reflective of abnormalities within visual systems. This is a preliminary finding that may suggest the utility of performing VEP analysis in a larger sample of SSADH-deficient patients, and encourage a neurophysiological assessment of GABA(C) receptor function in Aldh5a1(-/-) mice to reveal new pathophysiological mechanisms of this rare disorder of GABA degradation.
Journal of Inherited Metabolic Disease 05/2009; · 3.58 Impact Factor
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M. FRONTALI,
C. IODICE,
P. LULLI,
M. SPADARO,
S. CAPPELLACCI,
P. GIUNTI, P. MALASPINA,
M. MORELLINI,
C. MOROCUTTI,
A. NOVELLETTO,
F. PERSICHETTI,
S. TRABACE,
R. ANASTASI,
L. TERRENATO
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ABSTRACT: Two large Italian pedigrees with HLA-linked spinocerebellar ataxia (SCA1) were typed for HLA-A, -B and -DR as well as for markers either distal (F13A, D6S8) or proximal (D6S29, GLOl) to HLA. Pairwise linkage analyses of SCA1 vs. HLA-A, -B and -DR showed peak lodscores of 5-3, 5-6 and 3-3 respectively at 7 % recombination. Negative lodscores significantly excluded linkage with F13A at less than 5% and with GLOl at less than 10%. The lodscores with D6S8 and D6S29 had only low peaks.Recombination events in the two pedigrees and the estimated genetic distances of SCAl from GLOl and HLA favour the hypothesis of a SCA1 location distal to both of them. An order cen-GLOl-HLA-SCAl-tel appears therefore most likely with present data. These results are discussed in relation to previous reports placing SCA1 distal to HLA in two families and proximal in another.
Annals of Human Genetics 09/2007; 55(1):7 - 15. · 2.57 Impact Factor
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Neurology 05/2007; 68(16):1320-1. · 8.31 Impact Factor
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ABSTRACT: To analyze the contribution of the Czech population to the Y-chromosome diversity landscape of Europe and to reconstruct past demographic events, we typed 257 males from five locations for 21 UEPs. Moreover, 141 carriers of the three most common haplogroups were typed for 10 microsatellites and coalescent analyses applied. Sixteen Hg's characterized by derived alleles were identified, the most common being R1a-SRY(10831) and P-DYS257*(xR1a). The pool of haplogroups within I-M170 represented the third most common clade. Overall, the degree of population structure was low. The ages for Hg I-M170, P-DYS257*(xR1a), and R1a-SRY(10831) ap peared to be comparable and compatible with their presence during or soon after the LGM. A signal of population growth beginning in the first millennium B.C. was detected. Its similarity among the three most common Hg's indicated that growth was characteristic for a gene pool that already contained all of them. The Czech population appears to be influenced, to a very moderate extent, by genetic inputs from outside Europe in the post-Neolithic and historical times. Population growth postdated the archaeologically documented introduction of Neolithic technology and the estimated central value coincides with a period of repeated changes driven by the development of metal technologies and the associated social and trade organization.
American Journal of Physical Anthropology 02/2007; 132(1):132-9. · 2.82 Impact Factor
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P Blasi,
F Palmerio,
S Caldarola,
C Rizzo,
R Carrozzo,
K M Gibson,
A Novelletto,
F Deodato,
M Cappa,
C Dioni-Vici, P Malaspina
Clinical Genetics 04/2006; 69(3):294-6. · 3.13 Impact Factor
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C Capelli,
N Redhead,
V Romano,
F Calì,
G Lefranc,
V Delague,
A Megarbane,
A E Felice,
V L Pascali,
P I Neophytou,
Z Poulli,
A Novelletto, P Malaspina,
L Terrenato,
A Berebbi,
M Fellous,
M G Thomas,
D B Goldstein
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ABSTRACT: The Mediterranean region has been characterised by a number of pre-historical and historical demographic events whose legacy on the current genetic landscape is still a matter of debate. In order to investigate the degree of population structure across the Mediterranean, we have investigated Y chromosome variation in a large dataset of Mediterranean populations, 11 of which are first described here. Our analyses identify four main clusters in the Mediterranean that can be labelled as North Africa, Arab, Central-East and West Mediterranean. In particular, Near Eastern samples tend to separate according to the presence of Arab Y chromosome lineages, suggesting that the Arab expansion played a major role in shaping the current genetic structuring within the Fertile Crescent.
Annals of Human Genetics 04/2006; 70(Pt 2):207-25. · 2.57 Impact Factor
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ABSTRACT: We investigated the formation of complexes between cationic liposomes built up by DOTAP and three linear anionic polyions, with different charge density and flexibility, such as a single-stranded ssDNA, a double-stranded dsDNA and the polyacrylate sodium salt [NaPAA] of three different molecular weights. Our aim is to gain further insight into the formation mechanism of polyion-liposome aggregates of different sizes (lipoplexes), by comparing the behavior of DNA with a model polyelectrolyte, such as NaPAA, with approximately the same charge density but with a higher flexibility. We employed dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements, in order to explore both the hydrodynamic and structural properties of the aggregates resulting from polyion-liposome interaction and to present a comprehensive picture of the complexation process. The phenomenology can be summarized in a charge ratio-dependent scenario, where the main feature is the formation of large equilibrium clusters due to the aggregation of intact polyion-coated vesicles. At increasing polyion-liposome ratio, the size of the clusters continuously increases, reaching a maximum at a well-defined value of this ratio, and then decreases ("reentrant" condensation). The aggregation mechanism and the role of the polyion charge density in the complex formation are discussed in the light of the recent theories on the correlated adsorption of polyelectrolytes at charged interfaces. Within this framework, the phenomena of charge inversion and the reentrant condensation, peaked at the isoelectric point, finds a simple explanation.
Biochimica et Biophysica Acta 09/2005; 1714(1):11-24. · 4.66 Impact Factor
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F Di Giacomo,
F Luca,
L O Popa,
N Akar,
N Anagnou,
J Banyko,
R Brdicka,
G Barbujani,
F Papola,
G Ciavarella, [......],
V Mandarino,
C Mammi,
E N Michalodimitrakis,
G Paoli,
K I Pappa,
G Pedicini,
L Terrenato,
S Tofanelli, P Malaspina,
A Novelletto
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ABSTRACT: In order to attain a finer reconstruction of the peopling of southern and central-eastern Europe from the Levant, we determined the frequencies of eight lineages internal to the Y chromosomal haplogroup J, defined by biallelic markers, in 22 population samples obtained with a fine-grained sampling scheme. Our results partially resolve a major multifurcation of lineages within the haplogroup. Analyses of molecular variance show that the area covered by haplogroup J dispersal is characterized by a significant degree of molecular radiation for unique event polymorphisms within the haplogroup, with a higher incidence of the most derived sub-haplogroups on the northern Mediterranean coast, from Turkey westward; here, J diversity is not simply a subset of that present in the area in which this haplogroup first originated. Dating estimates, based on simple tandem repeat loci (STR) diversity within each lineage, confirmed the presence of a major population structuring at the time of spread of haplogroup J in Europe and a punctuation in the peopling of this continent in the post-Neolithic, compatible with the expansion of the Greek world. We also present here, for the first time, a novel method for comparative dating of lineages, free of assumptions of STR mutation rates.
Human Genetics 11/2004; 115(5):357-71. · 5.07 Impact Factor
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F Di Giacomo,
F Luca,
N Anagnou,
G Ciavarella,
R M Corbo,
M Cresta,
F Cucci,
L Di Stasi,
V Agostiano,
M Giparaki,
A Loutradis,
C Mammi,
E N Michalodimitrakis,
F Papola,
G Pedicini,
E Plata,
L Terrenato,
S Tofanelli, P Malaspina,
A Novelletto
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ABSTRACT: We explored the spatial distribution of human Y chromosomal diversity on a microgeographic scale, by typing 30 population samples from closely spaced locations in Italy and Greece for 9 haplogroups and their internal microsatellite variation. We confirm a significant difference in the composition of the Y chromosomal gene pools of the two countries. However, within each country, heterogeneity is not organized along the lines of clinal variation deduced from studies on larger spatial scales. Microsatellite data indicate that local increases of haplogroup frequencies can be often explained by a limited number of founders. We conclude that local founder or drift effects are the main determinants in shaping the microgeographic Y chromosomal diversity.
Molecular Phylogenetics and Evolution 10/2003; 28(3):387-95. · 3.61 Impact Factor
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ABSTRACT: Historical sources indicate that the evangelist Luke was born in Syria, died in Greece, and then his body was transferred to Constantinople, and from there to Padua, Italy. To understand whether there is any biological evidence supporting a Syrian origin of the Padua body traditionally attributed to Luke, or a replacement in Greece or Turkey, the mtDNA was extracted from two teeth and its control region was cloned and typed. The sequence determined in multiple clones is an uncommon variant of a set of alleles that are common in the Mediterranean region. We also collected and typed modern samples from Syria and Greece. By comparison with these population samples, and with samples from Anatolia that were already available in the literature, we could reject the hypothesis that the body belonged to a Greek, rather than a Syrian, individual. However, the probability of an origin in the area of modern Turkey was only insignificantly lower than the probability of a Syrian origin. The genetic evidence is therefore compatible with the possibility that the body comes from Syria, but also with its replacement in Constantinople.
Proceedings of the National Academy of Sciences 12/2001; 98(23):13460-3. · 9.68 Impact Factor
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P Malaspina,
M Tsopanomichalou,
T Duman,
M Stefan,
A Silvestri,
B Rinaldi,
O Garcia,
M Giparaki,
E Plata,
A I Kozlov, [......],
D Kovatchev,
M G Kerimova,
N Anagnou,
L Gavrila,
L Veneziano,
N Akar,
A Loutradis,
E N Michalodimitrakis,
L Terrenato,
A Novelletto
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ABSTRACT: In this work we focus on a microsatellite-defined Y-chromosomal lineage (network 1.2) identified by us and reported in previous studies, whose geographic distribution and antiquity appear to be compatible with the Neolithic spread of farmers. Here, we set network 1.2 in the Y-chromosomal phylogenetic tree, date it with respect to other lineages associated with the same movements by other authors, examine its diversity by means of tri- and tetranucleotide loci and discuss the implications in reconstructing the spread of this group of chromosomes in the Mediterranean area. Our results define a tripartite phylogeny within HG 9 (Rosser et al. 2000), with the deepest branching defined by alleles T (Haplogroup Eu10) or G (Haplogroup Eu9) at M172 (Semino et al. 2000), and a subsequent branching within Eu9 defined by network 1.2. Population distributions of HG 9 and network 1.2 show that their occurrence in the surveyed area is not due to the spread of people from a single parental population but, rather, to a process punctuated by at least two phases. Our data identify the wide area of the Balkans, Aegean and Anatolia as the possible homeland harbouring the largest variation within network 1.2. The use of recently proposed tests based on the stepwise mutation model suggests that its spread was associated to a population expansion, with a high rate of male gene flow in the Turkish-Greek area.
Annals of Human Genetics 08/2001; 65(Pt 4):339-49. · 2.57 Impact Factor
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ABSTRACT: Nine single nucleotide (SNP) or indel binary polymorphisms were used to determine the frequencies and phylogenetic relationships of 12 Y chromosomal haplogroups in 289 males from Romania and the Republic of Moldova. Our data indicated a low but not null rate of the homoplasic appearance of the DYZ3 (-) allelic state. All other markers confirmed the previously proposed phylogeny. Based on the affinities between populations in terms of haplogroup frequencies, this work identified the geographical region of the Carpathians as a break point in the gene geography of Eastern Central Europe, providing a finer definition of one of the possible sharp genetic changes between Western and Eastern Europe.
European Journal of HumanGenetics 02/2001; 9(1):27-33. · 4.40 Impact Factor
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Z H Rosser,
T Zerjal,
M E Hurles,
M Adojaan,
D Alavantic,
A Amorim,
W Amos,
M Armenteros,
E Arroyo,
G Barbujani, [......],
S Rootsi,
D C Rubinsztein,
J Saillard,
F R Santos,
G Stefanescu,
B C Sykes,
A Tolun,
R Villems,
C Tyler-Smith,
M A Jobling
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ABSTRACT: Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant clines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. Principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low, nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift.
The American Journal of Human Genetics 01/2001; 67(6):1526-43. · 10.60 Impact Factor
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P Malaspina,
F Cruciani,
P Santolamazza,
A Torroni,
A Pangrazio,
N Akar,
V Bakalli,
R Brdicka,
J Jaruzelska,
A Kozlov, [......],
M M Memmi,
G Vona,
R Villems,
J Parik,
V Romano,
M Stefan,
M Stenico,
L Terrenato,
A Novelletto,
R Scozzari
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ABSTRACT: We typed 1801 males from 55 locations for the Y-specific binary markers YAP, DYZ3, SRY10831 and the (CA)n microsatellites YCAII and DYS413. Phylogenetic relationships of chromosomes with the same binary haplotype were condensed in seven large one-step networks, which accounted for 95% of all chromosomes. Their coalescence ages were estimated based on microsatellite diversity. The three largest and oldest networks undergo sharp frequency changes in three areas. The more recent network 3.1A clearly discriminates between Western and Eastern European populations. Pairwise Fst showed an overall increment with increasing geographic distance but with a slope greatly reduced when compared to previous reports. By sectioning the entire data set according to geographic and linguistic criteria, we found higher Fst-on-distance slopes within Europe than in West Asia or across the two continents.
Annals of Human Genetics 10/2000; 64(Pt 5):395-412. · 2.57 Impact Factor
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R Scozzari,
F Cruciani,
P Santolamazza, P Malaspina,
A Torroni,
D Sellitto,
B Arredi,
G Destro-Bisol,
G De Stefano,
O Rickards,
C Martinez-Labarga,
D Modiano,
G Biondi,
P Moral,
A Olckers,
D C Wallace,
A Novelletto
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ABSTRACT: To define Y-chromosome haplotypes, we studied seven biallelic polymorphic sites. We combined data with those from four dinucleotide-repeat polymorphisms, to establish Y-chromosome compound superhaplotypes. Eight biallelic haplotypes that matched the dendrogram proposed by other investigators were identified in 762 Y chromosomes from 25 African populations. For each biallelic site, coalescence time of lineages carrying the derived allele was estimated and compared with previous estimates. The "ancestral" haplotype (haplotype 1A) was observed among Ethiopians, "Khoisan" (!Kung and Khwe), and populations from northern Cameroon. Microsatellite distributions within this haplotype showed that the Khoisan haplotypes 1A are widely divergent from those of the other two groups. Populations from northern Africa and northern Cameroon share a haplotype (i.e., 1C), which is not observed in other African populations but represents a major Eurasian cluster. Haplotypes 1C of northern Cameroon are clearly distinct from those of Europe, whereas haplotypes 1C of northern African are well intermingled with those of the other two groups. Apportionment of diversity for the Y-chromosomal biallelic haplotypes was calculated after populations were clustered into different configurations. Despite some correspondence between language affiliation and genetic similarity, geographic proximity seems to be a better predictor of genetic affinity.
The American Journal of Human Genetics 10/1999; 65(3):829-46. · 10.60 Impact Factor
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P Malaspina,
F Cruciani,
B M Ciminelli,
L Terrenato,
P Santolamazza,
A Alonso,
J Banyko,
R Brdicka,
O García,
C Gaudiano, [......],
P Mandich,
P Moral,
R Qamar,
S Q Mehdi,
A Ragusa,
G Stefanescu,
M Caraghin,
C Tyler-Smith,
R Scozzari,
A Novelletto
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ABSTRACT: In a study of 908 males from Europe, northern Africa, and western Asia, the variation of four Y-linked dinucleotide microsatellites was analyzed within three "frames" that are defined by mutations that are nonrecurrent, or nearly so. The rapid generation and extinction of new dinucleotide length variants causes the haplotypes within each lineage to diverge from one another. We constructed networks of "adjacent" haplotypes within each frame, by assuming changes of a single dinucleotide unit. Two small and six large networks were obtained, the latter including 94.9% of the sampled Y chromosomes. We show that the phenetic relationships among haplotypes, represented as a network, result largely from common descent and subsequent molecular radiation. The grouping of haplotypes of the same network thus fits an evolutionarily relevant criterion. Notably, this method allows the total diversity within a sample to be partitioned. Networks can be considered optimal markers for population studies, because reliable frequency estimates can be obtained in small samples. We present synthetic maps describing the incidence of different Y-chromosomal lineages in the extant human populations of the surveyed areas. Dinucleotide diversity also was used to infer time intervals for the coalescence of each network.
The American Journal of Human Genetics 10/1998; 63(3):847-60. · 10.60 Impact Factor
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ABSTRACT: Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare metabolic disorder of 4-aminobutyric acid degradation, has been identified in approximately 150 patients. Affected individuals accumulate large quantities of 4-hydroxybutyric acid, a compound with a wide range of neuropharmacological activities, in physiological fluids. As a first step in beginning an investigation of the molecular genetics of SSADH deficiency, we have utilized SSADH cDNA and genomic sequences to identify two point mutations in the SSADH genes derived from four patients. These mutations, identified by standard methods of reverse transcription, PCR, dideoxy-chain termination, and cycle sequencing, alter highly conserved sequences at intron/exon boundaries and prevent the RNA-splicing apparatus from properly recognizing the normal splice junction. Each family segregated a mutation in a different splice site, resulting in exon skipping and, in one case, a frameshift and premature termination and, in the other case, an in-frame deletion in the resulting protein. Family members, including parents and siblings of these patients, were shown to be heterozygotes for the splicing abnormality, providing additional evidence for autosomal recessive inheritance. Our results provide the first evidence that 4-hydroxybutyric aciduria, resulting from SSADH deficiency, is the result of genetic defects in the human SSADH gene.
The American Journal of Human Genetics 09/1998; 63(2):399-408. · 10.60 Impact Factor
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R Scozzari,
F Cruciani, P Malaspina,
P Santolamazza,
B M Ciminelli,
A Torroni,
D Modiano,
D C Wallace,
K K Kidd,
A Olckers, [......],
L Terrenato,
N Akar,
R Qamar,
A Mansoor,
S Q Mehdi,
G Meloni,
G Vona,
D E Cole,
W Cai,
A Novelletto
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ABSTRACT: The global pattern of variation at the homologous microsatellite loci DYS413 (Yq11) and DXS8174 and DXS8175 (Xp22) was analyzed by examination of 30 world populations from four continents, accounting for more than 1,100 chromosomes per locus. The data showed discordant patterns of among- and within-population gene diversity for the Y-linked and the X-linked microsatellites. For the Y-linked polymorphism, all groups of populations displayed high FST values (the correlation between random haplotypes within subpopulations, relative to haplotypes of the total population) and showed a general trend for the haplotypes to cluster in a population-specific way. This was especially true for sub-Saharan African populations. The data also indicated that a large fraction of the variation among populations was due to the accumulation of new variants associated with the radiation process. Europeans exhibited the highest level of within-population haplotype diversity, whereas sub-Saharan Africans showed the lowest. In contrast, data for the two X-linked polymorphisms were concordant in showing lower FST values, as compared with those for DYS413, but higher within-population variances, for African versus non-African populations. Whereas the results for the X-linked loci agreed with a model of greater antiquity for the African populations, those for DYS413 showed a confounding pattern that is apparently at odds with such a model. Possible factors involved in this differential structuring for homologous X and Y microsatellite polymorphisms are discussed.
The American Journal of Human Genetics 10/1997; 61(3):719-33. · 10.60 Impact Factor
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P Malaspina,
B M Ciminelli,
L Viggiano,
C Jodice,
F Cruciani,
P Santolamazza,
D Sellitto,
R Scozzari,
L Terrenato,
M Rocchi,
A Novelletto
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ABSTRACT: Four X-linked loci showing homology with a previously described Y-linked polymorphic locus (DYS413) were identified and characterized. By fluorescent in situ hybridization (FISH), somatic cell hybrids, and YAC screening, the X-linked members of this small family of sequences (CAIII) all map in Xp22, while the Y members map in Yq11. These loci contribute to the overall similarity of the two genomic regions. All of the CAIII loci contain an internal microsatellite of the (CA)n type. The microsatellites display extensive length polymorphism in two of the X-linked members as well as in the Y members. In addition, common sequence variants are found in the portions flanking the microsatellites in two of the X-linked members. Our results indicate that, during the evolution of this family, length variation on the Y chromosome was accumulated at a rate not slower than that on the X chromosome. Finally, these sequences represent a model system with which to analyze human populations for similar X- and Y-linked polymorphisms.
Journal of Molecular Evolution 07/1997; 44(6):652-9. · 2.27 Impact Factor
