CYP1A1 Variability In Human Populations

The human cytochrome P4501A1 (CYP1A1) enzyme plays an important role in the metabolism of xenobiotics and endogenous substrates. Because polymorphisms within the CYP1A1 gene have been shown to be associated with various cancer risks and with the predicting clinical efficacy of some chemotherapies in different populations, most studies focus on their clinical significance. We, however, were interested in evaluating whether the polymorphisms could be used to distinguish human populations. Four single nucleotide CYP1A1 polymorphisms (rs4646903/ g.75011641; rs1048943/g.75012985; g.75012235; and rs1799814/ g.75012987) were analysed via PCR-RFLP assay in 1,195 individuals of various human groups from all over the world. In order to gain a more complete view of the genetic variability of the CYP1A1 gene, different statistical analyses were performed upon the populations of the present study and upon the limited data gleaned from previously studied populations. The allele and haplotype frequencies vary among populations: the rs4646903 (C) and rs1048943 (G) have been found to be nearly always linked and were found at the highest frequencies in Native Americans, while the variant associated to the position g.75012235 was only detected in certain African populations. Our work clearly indicates that the CYP1A1 polymorphisms differ among populations and that the prediction of genotypes constitutes an important aspect of precision medicine since some variants were associated with certain cancers and rs1048943 show strong association with optimized chemotherapy. Moreover, the CYP1A1 gene plays an important role in the metabolism of xenobiotics and it is likely that its frequencies could be strongly influenced by environmental factors

The Genetic Landscape of Serbian Populations through Mitochondrial DNA Sequencing and Non-Recombining Region of the Y Chromosome Microsatellites

The Balkan Peninsula is known to represent a complex cultural mosaic and it is a strategic area because it represents a gateway into Europe from the Near East. This research seeks to evaluate the variability of both uniparental markers (mtDNA and non-recombining region of the Y chromosome) to dissect the genetic makeup of Serbians. The whole sample pertains to 257 Serbians (87 from the central region and 170 from the southern area) who have been analyzed for both uniparental genetic markers. The results showed that the extant inhabitants of the Balkan Peninsula have a homogeneous genetic background, despite their linguistic and cultural differences. The obtained data were compared with those of neighboring populations to detect possible relationships among groups. On the whole, the genetic variability of the Balkan populations seems to be due to an admixture process of European and Asian lineages in different proportions whose contributions constitute the current maternal and paternal genetic landscape

Carenza congenita di alfa 1 antitripsina. Una malattia rara o raramente diagnosticata?

II test di laboratorio stanno assumendo un’importanza sempre maggiore nella pratica clinica poiché sono spesso determinanti per orientare il percorso diagnostico e per scegliere e monitorare una corretta terapia. La possibilità di poter utilizzare test molecolari ha inoltre dato un nuovo risalto a test routinari di laboratorio che erano stati in parte sottovalutati. L’esempio che riportiamo in questa nota riguarda la diagnosi di una malattia metabolica, considerata rara, che è associata a diversi tipi di patologie soprattutto polmonari ed epatiche: la carenza congenita di alfa 1 antitripsina. L’Alfa-1-AntiTripsina (AAT) è una glicoproteina serica del peso di 52 KD, la cui concentrazione va normalmente dai 100 ai 130 mg/dl e costituisce più del 90% della banda delle alfa-1-globuline in un normale protidogramma elettroforetico. È una proteina della fase acuta appartenente alla famiglia delle Serpine («Serine Protease Inihbitors »), ovvero proteine che inibiscono le serino proteasi. L’azione antiproteasica dell’A1AT è rivolta prevalentemente contro l’elastasi neutrofila (EN), proteasi coinvolta nel rimaneggiamento delle fibre elastiche che compongono la matrice connettivale. L’AAT viene prodotta normalmente nel fegato, nei monociti, nei macrofagi alveolari e nel pancreas esocrino(1) ma, solo gli epatociti hanno capacità secretiva Giornalmente vengono rilasciati in circolo circa 2 g di AAT e la molecola possiede una emivita di circa 4-5 giorni. La sua sintesi aumenta in risposta a vari stimoli, quali stati infiammatori, neoplasie, estrogeni, interventi chirurgici, interleuchina 6 e oncostatina-M (l’AAT aumenta in certe neoplasie). Una volta secreta, la proteina diffonde in numerosi organi dove protegge le strutture extra-cellulari dall’attacco dell’elastasi rilasciata dai neutrofili attivati o senescenti. (1). La patogenesi dell’enfisema polmonare nel deficit di AAT (DAAT) è legata ai ridotti valori plasmatici della proteina che, quindi, non è in grado di modulare l’azione dell’elastasi rilasciata dai neutofili negli alveoli polmonari, con conseguente distruzione dei setti interalveolari. Un importante cofattore nella patogenesi dell’enfisema polmonare nei pazienti affetti da DAAT è rappresentato dal fumo di sigaretta che determina l’inattivazione dell’AAT presente negli alveoli attraverso un processo di ossidazione. Poiché il danno polmonare nei pazienti affetti da DAAT è legato ai bassi valori sierici della glicoproteina, la terapia sostitutiva con somministrazione endovenosa di AAT umana parzialmente purificata è in grado di contrastare l’insorgenza dell’enfisema polmonare (2). A differenza di ciò che avviene a livello polmonare, il danno epatico è legato all’azione tossica esercitata dall’AAT mutata che si accumula nelle cisterne del reticolo endoplasmatico rugoso (RER) degli epatociti, principale sito di sintesi della proteina. La proteina mutata presenta, rispetto alla proteina normale, una configurazione tridimensionale alterata. Ciò favorisce la sua polimerizzazione all’interno del RER, determinando un ritardo nella successiva tappa di rilascio e secrezione della proteina e il suo accumulo all’interno del RER (3)

Mitochondrial variability in the Mediterranean area: a complex stage for human migrations

Context: The Mediterranean area has always played a significant role in human dispersal due to the large number of migratory events contributing to shape the cultural features and the genetic pool of its populations. Objective: This paper aims to review and diachronically describe the mitogenome variability in the Mediterranean population and the main demic diffusions that occurred in this area over time. Methods: Frequency distributions of the leading mitochondrial haplogroups have been geographically and chronologically evaluated. The variability of U5b and K lineages has been focussed to broaden the knowledge of their genetic histories. Results: The mitochondrial genetic makeup of Palaeolithic hunter-gatherers is poorly defined within the extant Mediterranean populations, since only a few traces of their genetic contribution are still detectable. The Neolithic lineages are more represented, suggesting that the Neolithic revolution had a marked effect on the peopling of the Mediterranean area. The largest effect, however, was provided by historical migrations. Conclusion: Although the mitogenome variability has been widely used to try and clarify the evolution of the Mediterranean genetic makeup throughout almost 50 000 years, it is necessary to collect whole genome data on both extinct and extant populations from this area to fully reconstruct and interpret the impact of multiple migratory waves and their cultural and genetic consequences on the structure of the Mediterranean populations

Leopoli-Cencelle (9th–15th centuries CE), a centre of Papal foundation: bioarchaeological analysis of the skeletal remains of its inhabitants

Background The medieval city of Leopoli-Cencelle (9th–15th centuries CE) represents an exceptional study-model for extending our knowledge of the Italian Medieval period due not only to the large sample size available but also to the widespread presence of material data and a well preserved archaeological context. Aim This research aims to reconstruct the osteobiography of the inhabitants of this centre of Papal foundation. Subjects and methods The analysed sample counts 877 individuals. Scientifically established anthropological morphological methods were used for assessing their biological profile as well as for reconstructing lifestyle and health status. Results The sample consists of 62.49% adults and 37.51% non-adults. The mortality pattern shows the highest peak prior to 1 year and between 1 and 6 years of age and a reduced longevity of female individuals as commonly observed in pre-antibiotic era populations. Metric and musculoskeletal stress markers revealed different biomechanical stress between sexes probably carrying out different working activities. The palaeopathological analysis supports a general good health status with the exception of a few specific cases. Conclusions The present research helps shed light on the lifestyle of the inhabitants of Leopoli-Cencelle, enhancing a better understanding of the Italian Middle Ages

Mitochondrial characterisation of two Spanish populations from the Vera and Bejar valleys (Central Spain)

This survey reports the mitochondrial data of two Spanish populations living in the Vera and Bejar valleys, on the opposite slopes of the Sierra de Gredos (Central Spain), which crosses Spain east to west. The aim of the study was to characterise the mitochondrial genetic pool of the Vera and Bejar populations to investigate a putative mitogenetic differentiation between them, evidence that would support the role of the Sierra de Gredos as a genetic barrier in their micro-evolutionary histories. Blood samples of 137 people (66 from Vera and 71 from Bejar) were collected and mtDNA hypervariable regions I and II (HVR-I and HVR-II) were dissected along with several mtDNA-coding region SNPs. The main European mitochondrial lineages have been found both in Vera and in Bejar, together with the typical African haplogroups L (in Vera) and U6 (in Bejar). FST value and the 95% credible regions calculated for haplogroup frequencies do not reveal genetic differentiation among the populations. Vera and Bejar contain an expected mitochondrial variability within them, but they do not seem to be genetically different from each other, leading us to conclude that the Sierra de Gredos is not a significant genetic barrier in their maternal genetic history

Genetic history of the population of Sicily

We investigated the genetic heterogeneity of 2354 individuals from the 9 provinces of Sicily. The genetic markers we used were HP, GC, TF, PI, and AK1 plus other previously tested polymorphisms, for a total of 24 independent markers. Distinct multivariate statistics were applied to verify the claimed genetic distinctiveness between extant eastern and western Sicilian populations. Our hypothesis stated that any diversity found between the two subpopulations would represent the signature of early colonization of the island by Creek and Phoenician peoples. Correspondence analysis showed that there was no clear geographic clustering within Sicily. The genetic distance matrix used for identifying the main genetic barriers revealed no east-west differences within the island's population, at least at the provincial level. F-ST estimates proved that the population subdivision did not affect the pattern of gene frequency variation; this implies that Sicily is effectively one panmictic unit. The bulk of our results confirm the absence of genetic differentiation between eastern and western Sicilians, and thus we reject the hypothesis of the subdivision of an ancient population in two areas

Studio delle linee mitocondriali in due comunità del centro della Penisola Iberica: Bejar e Vera

Scopo di questo lavoro è stato quello di indagare la storia genetica per via materna di due comunità della Spagna centrale: Bejar e Vera, che secondo i dati archeologici e storici sembrano aver avuto una diversa storia demografica e genetica. Sono state studiate le sequenze dei segmenti HVS-I e HVS-II della regione di controllo del D-loop e alcuni SNPs della zona codificante del DNA mitocondriale in 137 individui (Bejar=71; Vera=66) non imparentati, i cui nonni, materni e paterni, erano nati in queste comunità. Ciascun aplotipo identificato è stato classificato e assegnato a un aplogruppo secondo la classificazione proposta da van Owen e Kaiser. E’ stata condotta l’analisi popolazionistica al fine di evidenziare eventuali affinità genetiche tra le diverse popolazioni della Penisola Iberica. Gli aplotipi appartenenti all’aplogruppo H sono stati ulteriormente classificati saggiando gli SNPs diagnostici. Le linee non attribuibili ad alcun sottoaplogruppo di H sono state sottoposte all’analisi di sequenza dell’intero genoma mitocondriale. Infine, è stato costruito un Median Joining network di tutti gli aplotipi H1 con lo scopo di evidenziare eventuali correlazioni geografiche tra i profili dei campioni da noi analizzati e altri descritti nella letteratura

Ancient genomes from a rural site in Imperial Rome (1st–3rd cent. CE): a genetic junction in the Roman Empire

Background Rome became the prosperous Capital of the Roman Empire through the political and military conquests of neighbouring areas. People were able to move Romeward modifying the Rome area’s demographic structure. However, the genomic evidence for the population of one of the broadest Empires in antiquity has been sparse until recently. Aim The genomic analysis of people buried in Quarto Cappello del Prete (QCP) necropolis was carried out to help elucidate the genomic structure of Imperial Rome inhabitants. Subjects and methods We recruited twenty-five individuals from QCP for ancient DNA analysis through whole-genome sequencing. Multiple investigations were carried out to unveil the genetic components featuring in the studied samples and the community’s putative demographic structure. Results We generated reliable whole-genome data for 7 samples surviving quality controls. The distribution of Imperial Romans from QCP partly overlaps with present-day Southern Mediterranean and Southern-Near Eastern populations. Conclusion The genomic legacy with the south-eastern shores of the Mediterranean Sea and the Central and Western Northern-African coast funerary influence pave the way for considering people buried in QCP as resembling a Punic-derived human group

The tale of Henry VII: a multidisciplinary approach to determining the post-mortem practice

During the Middle Ages in Europe, a different post-mortem funerary custom came to be used in order to transport and solemnly dispose of the bodies of high-status individuals. Because of their high degree of mobility, most medieval kings and queens rarely died where they had planned to be buried; thus, they had to be moved to the place of burial. Ancient writings describe some post-mortem funerary practices carried out to facilitate transport, such as boiling or burning of bodies after death. The remains of Henry VII of Luxembourg were analysed in order to determine which post-mortem practices were utilized. A detailed chemical-physical analysis was conducted to highlight the changes in the bone matrix due to post-mortem alteration. Boiling and burning leave different marks in the bone that could be differentiated through the analysis of the inorganic and organic components of the bone. Accordingly, anthropological, X-ray diffraction (XRD), infrared spectroscopy (FT-IR), collagen ratio, and scanning electron microscopy (FE-SEM/EDAX) analysis were performed on two different bone fragments: cranial and tibial shaft. This multidisciplinary approach has enriched scientific understanding of the post-mortem practices to which the skull and tibial shaft of Henry VII were subjected. The results highlight that the tibial shaft was treated under higher temperature respect to the skull. Furthermore, this analysis also shed light on the state of preservation of the bone fragments analysed and has allowed us to initiate more complex molecular analysis, as well as ancient DNA analysis