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A Di Rienzo

Publications and source records attributed to A Di Rienzo.

At least 19 recordsLinked to original sources
PubMed2005

Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants.

A positional cloning study of type 2 diabetes in Mexican Americans identified a region, termed "NIDDM1," on chromosome 2q37 with significant linkage evidence. Haplotype combinations at the calpain-10 gene (CAPN10) within this region were shown to increase diabetes risk in several populations. On the basis of the thrifty genotype hypothesis, variants that increase susceptibility to type 2 diabetes under modern lifestyle conditions provided a survival advantage in past environments by increasing the efficiency of energy use and storage. Here, our goal is to make inferences about the evolutionary forces shaping variation in genes in the NIDDM1 region and to investigate the population genetics models that may underlie the thrifty genotype hypothesis. To this end, we surveyed sequence variation in CAPN10 and in an adjacent gene, G-protein-coupled receptor 35 (GPR35), in four population samples from different ethnic groups. These data revealed two distinct deviations from the standard neutral model in CAPN10, whereas GPR35 variation was largely consistent with neutrality. CAPN10 showed a significant deficit of variation in the haplotype class defined by the derived allele at SNP44, a polymorphism that is significantly associated with diabetes in meta-analysis studies. This suggests that this haplotype class was quickly driven to high frequency by positive natural selection. Interestingly, the derived allele at SNP44 is protective against diabetes. CAPN10 also showed a local excess of polymorphism and linkage disequilibrium decay in intron 13. Simulations show that this pattern may be explained by long-standing balancing selection that maintains multiple selected alleles. Alternatively, it is possible that the local mutation and recombination rates changed since the divergence of human and chimpanzee; this scenario does not require the action of natural selection on intron 13 variation.

Calpain↗
PubMed2005

Supratentorial cavernomas in eloquent brain areas: application of neuronavigation and functional MRI in operative planning.

AIM: Cavernomas located in eloquent areas of cerebral hemispheres represent a challenge for the neurosurgeon. An accurate surgical approach is essential to completely remove the lesion with function preservation. Aim of this study was to evaluate the usefulness of integration between standard magnetic resonance imaging (MRI) for neuronavigation and functional MRI (fMRI) in preoperative planning and intraoperative removal of cavernomas. METHODS: Between June 2000 and December 2002, 21 patients underwent surgery for supratentorial subcortical cavernomas. Eleven lesions were located adjacent to eloquent brain areas. All the patients in the series underwent MRI for neuronavigation and, since January 2002, in 6 cases of lesions located in eloquent areas, fMRI was also performed, with subsequent images fusion. The surgical approach was performed via the transgyral route under conventional and ultrasound-guided neuronavigation. RESULTS: All the lesions were totally removed. No morbidity was seen in patients harbouring lesions in non eloquent areas. Four patients with lesions in critical areas suffered transient focal deficits, but only one patient of this series was operated on by the auxilium of image fusion. In 7 patients operated on by conventional image-guided surgery and affected by preoperative seizures, no further seizures were observed after surgery. In 3 patients more hosting lesions neighbouring critical areas, the perilesional ring was not removed, observing persistence of seizures pharmacologically treated. In 4 of the 6 patients (all affected by seizures), operated on by fMRI auxilium, lesion removal was associated to the removal of the perilesional ring. No further epilepsy was seen in these patients. CONCLUSIONS: In all the cases the use of neuronavigation allowed minimally invasive approaches and radical excision of the lesions. Moreover, fMRI seemed to provide important additional information in patients with lesions in eloquent brain areas, allowing a more aggressive approach on the perilesional tissue to the aim of resolving seizures, in absence of an increase in the morbidity rate.

Adolescent↗
PubMed2004

CYP3A variation and the evolution of salt-sensitivity variants.

Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude.

Black or African American↗
PubMed2004

The interhemispheric transcallosal-transversal approach to the lesions of the anterior and middle third ventricle: surgical validity and neuropsychological evaluation of the outcome.

Based on the observation of the course of callosal fibres and of their artero-venous support as appearing in a microanatomic study, the Authors propose a variant of standard callosotomy procedure by the introduction of the transverse section of callosal fibres. This technique would allow the surgeon to spare a larger number of callosal fibres by the combined effect of a lower direct mechanical traction on fibres and a lower impact on artero-venous microcircle. The neuropsychological outcome of the patients who underwent this kind of procedure was evaluated. Fourteen patients affected by occupying-space lesions involving the anterior and middle third ventricle were included in the study. Ten patients underwent transverse callosotomy, four subjects received standard sagittal callosotomy. A control group was also included in the study. All patients underwent a pre-operative and six months post-operative neuropsychological evaluation focused on performance at cognitive and attentional tasks. No disturbances in executive function were observed in either group. Patients receiving transverse callosotomy performed as well as control group subjects in attentive tasks, which is not the case of patients undergoing sagittal callosotomy who show a marked deficit in selective attention for left side visual field. The observed more favourable neuropsychological outcome supports transverse callosotomy as a valid alternative method to standard longitudinal callosotomy in third ventricle surgery.

Adult↗
PubMed2001

Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels.

To characterize linkage disequilibrium (LD) levels in human populations, we have analyzed 10 independent noncoding segments in three population samples from the major ethnic groups--that is, Africans, Asians, and Europeans. Descriptive statistics show that LD decays much faster in the African samples than in the non-African ones. With the assumption of an equilibrium model, we estimated the population crossing-over parameter (4N(e)r(bp), where N(e) is the effective population size and r(bp) is the crossing-over rate per generation between adjacent base pairs) in the presence of gene conversion. In the African sample, LD and polymorphism levels lead to similar estimates of effective population size, as expected under an equilibrium model. Conversely, in both non-African samples, LD levels suggest a smaller effective population size than that implied by polymorphism levels. This observation is paralleled by significant departures from an equilibrium model in the spectrum of allele frequencies of the non-African samples. Besides ruling out the possibility that non-African populations are at equilibrium, these results suggest different demographic history (temporal and spatial) of these groups. Interestingly, the African sample fits the expectations of an equilibrium model based on polymorphism and divergence levels and on frequency spectrum. For this sample, the estimated ratio of gene conversion to crossing-over rates is 7.3 for a mean tract length of 500 bp, suggesting that gene conversion may be more frequent than previously thought. These findings imply that disease-association studies will require a much denser map of polymorphic sites in African than in non-African populations.

Africa↗
PubMed2001

A population genetics study of single nucleotide polymorphisms in the interleukin 4 receptor alpha (IL4RA) gene.

Interleukin 4 (IL4) plays a critical role in T helper 2 (Th2) immune responses. Here we report a population genetics study of variation in the gene encoding the alpha-chain of the IL4 receptor (IL4RA) in three ethnic groups: African Americans, European Americans and East Asians. A 2941-bp region spanning exon 12 of IL4RA gene was sequenced in 12 individuals from each group. A total of 24 single nucleotide polymorphisms (SNPs) were identified in the combined sample. The genetic variation of the coding region of exon 12 is two to three times higher than in other reported genes. A significant departure from the expectation of evolutionary neutrality was observed, suggesting that natural selection may have influenced the evolution of this gene. We propose a model in which past selection by pathogens contributed to the increasing prevalence of atopic disorders in Western societies.

Black or African American↗
PubMed2001

Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans.

The Toll-like receptor 4 protein acts as the transducing subunit of the lipopolysaccharide receptor complex and assists in the detection of Gram-negative pathogens within the mammalian host. Several lines of evidence support the view that variation at the TLR4 locus may alter host susceptibility to Gram-negative infection or the outcome of infection. Here, we surveyed TLR4 sequence variation in the complete coding region (2.4 kb) in 348 individuals from several population samples; in addition, a subset of the individuals was surveyed at 1.1 kb of intronic sequence. More than 90% of the chromosomes examined encoded the same structural isoform of TLR4, while the rest harbored 12 rare amino acid variants. Conversely, the variants at silent sites (intronic and synonymous positions) occur at both low and high frequencies and are consistent with a neutral model of mutation and random drift. The spectrum of allele frequencies for amino acid variants shows a significant skew toward lower frequencies relative to both the neutral model and the pattern observed at linked silent sites. This is consistent with the hypothesis that weak purifying selection acted on TLR4 and that most mutations affecting TLR4 protein structure have at least mildly deleterious phenotypic effects. These results may imply that genetic variants contributing to disease susceptibility occur at low frequencies in the population and suggest strategies for optimizing the design of disease-mapping studies.

Alleles↗
PubMed2001

Radial nerve palsy caused by spontaneously occurring nerve torsion. Case report.

An 18-year-old man presented with a spontaneously occurring radial nerve palsy that spared the triceps muscle. At surgery, the portion of the radial nerve located at the midarm level had an hourglass-like appearance. Under magnification, an external-internal neurolysis of the narrowed portion of the hourglass-shaped portion revealed nerve torsion. Straightening of the twisted nerve and fixation accomplished using epiperineurium-fascia stitches to avoid a new torsion resulted in complete functional recovery of the radial nerve.

Adolescent↗
PubMed2000

Tracing European founder lineages in the Near Eastern mtDNA pool.

Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2, 804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

DNA, Mitochondrial↗
PubMed2000

Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus.

The Duffy blood group locus, which encodes a chemokine receptor, is characterized by three alleles-FY*A, FY*B, and FY*O. The frequency of the FY*O allele, which corresponds to the absence of Fy antigen on red blood cells, is at or near fixation in most sub-Saharan African populations but is very rare outside Africa. The FST value for the FY*O allele is the highest observed for any allele in humans, providing strong evidence for the action of natural selection at this locus. Homozygosity for the FY*O allele confers complete resistance to vivax malaria, suggesting that this allele has been the target of selection by Plasmodium vivax or some other infectious agent. To characterize the signature of directional selection at this locus, we surveyed DNA sequence variation, both in a 1.9-kb region centered on the FY*O mutation site and in a 1-kb region 5-6 kb away from it, in 17 Italians and in a total of 24 individuals from five sub-Saharan African populations. The level of variation across both regions is two- to threefold lower in the Africans than in the Italians. As a result, the pooled African sample shows a significant departure from the neutral expectation for the number of segregating sites, whereas the Italian sample does not. The FY*O allele occurs on two major haplotypes in three of the five African populations. This finding could be due to recombination, recurrent mutation, population structure, and/or mutation accumulation and drift. Although we are unable to distinguish among these alternative hypotheses, it is likely that the two major haplotypes originated prior to selection on the FY*O mutation.

Africa South of the Sahara↗
PubMed2000

Adjusting the focus on human variation.

Studies of nuclear sequence variation are accumulating, such that we can expect a good description of the structure of human variation across populations and genomic regions in the near future. This description will help to elucidate the evolutionary forces that shape patterns of variability. Such an understanding will be of general biological interest, but could also facilitate the design and interpretation of disease-mapping studies. Here, we integrate the results from surveys of nuclear sequence variation. When nuclear sequences are considered together with mtDNA and microsatellites, it becomes clear that neither the standard neutral model, nor a simple long-term exponential growth model, can account for all the available human variation data. A possible explanation is that a subset of loci are not evolving neutrally; even so, more-complex models of effective population size and structure might be necessary to explain the data.

Biological Evolution↗
PubMed2000

Microsatellite mutations and inferences about human demography.

Microsatellites have been widely used as tools for population studies. However, inference about population processes relies on the specification of mutation parameters that are largely unknown and likely to differ across loci. Here, we use data on somatic mutations to investigate the mutation process at 14 tetranucleotide repeats and carry out an advanced multilocus analysis of different demographic scenarios on worldwide population samples. We use a method based on less restrictive assumptions about the mutation process, which is more powerful to detect departures from the null hypothesis of constant population size than other methods previously applied to similar data sets. We detect a signal of population expansion in all samples examined, except for one African sample. As part of this analysis, we identify an "anomalous" locus whose extreme pattern of variation cannot be explained by variability in mutation size. Exaggerated mutation rate is proposed as a possible cause for its unusual variation pattern. We evaluate the effect of using it to infer population histories and show that inferences about demographic histories are markedly affected by its inclusion. In fact, exclusion of the anomalous locus reduces interlocus variability of statistics summarizing population variation and strengthens the evidence in favor of demographic growth.

Colorectal Neoplasms↗
PubMed2000

[Recurrent laryngeal nerve and inferior thyroid artery. Anatomo-surgical considerations].

Among the diverse complications of thyroidectomy, it is mostly the cordial sequels from the recurrent laryngeal nerve damage. This is why anatomical and surgical considerations are made upon the vulnerable areas of this nerve and the circumstances in which it is damaged. The relationship between the recurrent laryngeal nerve and the inferior thyroid artery, location most frequently injured, was investigated on 55 adult formulated cadavers. It was found that on the right side in 54.5% the nerve passes behind the artery, in 38.1% it passes in front of it, and between its terminal branches in 7.2%. Regarding the left side, in 67.2% the nerve passes behind the artery, in 27.2% it does so in front of it, and in 5.4% between its terminal branches; being the right nerve more anterior an lateral than the left one which would possibly explain the higher index of nervous damage on this side.

Adult↗
PubMed1999

Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism.

BACKGROUND: Hepatic uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1 (UGT1A1) is primarily responsible for the glucuronidation of SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of the anticancer agent irinotecan. UGT1A1, also catalyzing the glucuronidation of bilirubin, has been shown to have reduced activity in Gilbert's syndrome. The presence of an additional TA repeat [(TA)7TAA] in the TATA sequence of UGT1A1 has been associated with Gilbert's syndrome. OBJECTIVE: To evaluate the relationship between UGT1A1 phenotypic activity and UGT1A1 promoter polymorphism. METHODS: Phenotypic measurements included in vitro SN-38 and bilirubin glucuronidation in human liver microsomes (n = 44). A recently developed genotyping test was used to determine TATA sequence polymorphisms in UGT1A1. Genotypes were assigned as follows: 7/7, homozygous for the (TA)7TAA allele; 6/6, homozygous for the (TA)6TAA allele; and 6/7, heterozygous with 1 of each allele. RESULTS: Nine percent of screened liver samples were found to be homozygous for allele 7 (7/7), 43% were homozygous for allele 6 (6/6), and 48% were heterozygous (6/7). Frequencies of (TA)7TAA and (TA)6TAA alleles were 0.33 and 0.67, respectively. A significant trend toward a decrease in SN-38 and bilirubin glucuronidation rates was found as the number of TA repeats increased (6/6 > 6/7 > 7/7). Glucuronidation rates of both substrates were significantly lower in the 7/7 and 6/7 groups compared with the 6/6 group. CONCLUSIONS: The results indicate a significant association of UGT1A1 phenotype and genotype based on in vitro phenotypic measurements. The clinical significance of our finding remains to be established.

Antineoplastic Agents, Phytogenic↗
PubMed1999

mtDNA analysis of Nile River Valley populations: A genetic corridor or a barrier to migration?

To assess the extent to which the Nile River Valley has been a corridor for human migrations between Egypt and sub-Saharan Africa, we analyzed mtDNA variation in 224 individuals from various locations along the river. Sequences of the first hypervariable segment (HV1) of the mtDNA control region and a polymorphic HpaI site at position 3592 allowed us to designate each mtDNA as being of "northern" or "southern" affiliation. Proportions of northern and southern mtDNA differed significantly between Egypt, Nubia, and the southern Sudan. At slowly evolving sites within HV1, northern-mtDNA diversity was highest in Egypt and lowest in the southern Sudan, and southern-mtDNA diversity was highest in the southern Sudan and lowest in Egypt, indicating that migrations had occurred bidirectionally along the Nile River Valley. Egypt and Nubia have low and similar amounts of divergence for both mtDNA types, which is consistent with historical evidence for long-term interactions between Egypt and Nubia. Spatial autocorrelation analysis demonstrates a smooth gradient of decreasing genetic similarity of mtDNA types as geographic distance between sampling localities increases, strongly suggesting gene flow along the Nile, with no evident barriers. We conclude that these migrations probably occurred within the past few hundred to few thousand years and that the migration from north to south was either earlier or lesser in the extent of gene flow than the migration from south to north.

DNA Mutational Analysis↗
PubMed1999

Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates.

Variation at the UDP-glucuronosyltransferase (UGT) 1A1 gene promoter is present in humans. Variable numbers of TA repeats in the TATA box of this gene are found which are inversely related to levels of gene expression. We investigated this polymorphism in 658 individuals from a worldwide sample of 15 aboriginal and two admixed human populations. This study shows that there is a great deal of variability across ethnic groups with regard to UGT1A1 allele frequencies, with the most common allele varying in frequency from 33% to 91%. Populations of African origin harbor four different alleles while non-African populations appear to have only two alleles. In addition, alleles associated with lower gene expression levels reach the highest frequencies in populations of African origin and lowest among Asians and Amerindians. Thus, more variability in the metabolism of drugs eliminated by UGT1A1 glucuronidation should be expected in populations of Sub-Saharan African origin. The sequence analysis of nine primate species shows that the number of TA repeats has increased during primate evolution achieving the largest number in humans. We suggest that the UGT1A1 promoter variability does not reflect historical relationships between populations and that it may be maintained by natural selection. Our findings are consistent with the proposal that the TA repeat variation is a balanced polymorphism.

Africa↗