Analysis of 31 STR loci in the genetic isolate of Carloforte (Sardinia, Italy)

The genotypes of 31 autosomal short tandem repeat loci in the population of Carloforte were analyzed, these representing a linguistic and genetic isolate located on the island of Sardinia (Italy). The markers span the entire length of chromosomes 19, 20, 21 and 22. Allele frequencies and statistical parameters were presented for all loci. Observed heterozygosity ranged from 0.279 to 0.884, and polymorphism information content from 0.552 to 0.886. All but two loci showed Hardy-Weinberg equilibrium after Bonferroni correction. The 31 short tandem repeat loci examined in the present work provide additional data on the genetic structure of the Carloforte population

Haplotype affinities resolve a major component of goat (<i>Capra hircus</i>) MtDNA D-loop diversity and reveal specific features of the Sardinian stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity. We identified haplotype groups overrepresented in Sardinian goats as a result of founder effects. We found that breeders maintain diversity of matrilines most likely through equalization of the reproductive potential. Moreover, the relevant amount of inter-farm mtDNA diversity found does not increase proportionally with distance. Our results illustrate the effects of breeding practices on the composition of maternal gene pool and identify mtDNA types that may be considered in projects aimed at retrieving the maternal component of the oldest breeds of Sardinia.</br

Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers

It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (A beta)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer's disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (e4) non-carriers. In addition, in e4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of A beta 1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF A beta 1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased A beta 1-40 and A beta 1-42 fragments in a cell line model of A beta production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don't carry the e4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.National Institute on Aging (NIA); National Alzheimer's Coordinating Center (NACC) [U01 AG016976]; National Institute on Aging: Ruth Seemann, John Hopkins Alzheimer's Disease Research Center (NIA) [AG05146, P50 AG16570, AG05128]; NINDS [NS39764]; Glaxo Smith Kline [P50-AG053760, AG05144, P50AG05681, P50 AG05136, P30-AG13846, 211002]; Arizona Biomedical Research Commission [4001, 0011, 05_ 901]; Michael J. Fox Foundation [AG10161, HHSN-271-2013-00030C]; McGowan Endowment; Medical Research Council, local NHS trusts and Newcastle University; Medical Research Council; Safa Al-Sarraj; Netherlands Brain Bank; Stichting MS Research, Brain Net Europe; Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds; Internationale Stiching Alzheimer Onderzoek; NIH-NIA [R01-AG041232]; State of Arizona DHS (Arizona Alzheimer's Consortium) - NIH EUREKA [R01-AG034504]; NIH intramural funds; UK Dementia Research Institute; DRI Ltd - UK Medical Research Council; Alzheimer's Society; Alzheimer's Research UK - Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer'sAssociation; Alzheimer's Drug Discovery Foundation; Araclon Biotech; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Fujirebio; Johnson & Johnson Pharmaceutical Research & Development LLC.; Merck Co., Inc.; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Takeda Pharmaceutical Company; Canadian Institutes of Health Research isproviding funds; ADNI clinical sites in Canada; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; Laboratory for Neuro Imaging at the University of Southern CaliforniaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A review of the main genetic factors influencing the course of COVID-19 in Sardinia: the role of human leukocyte antigen-G

Introduction: A large number of risk and protective factors have been identified during the SARS-CoV-2 pandemic which may influence the outcome of COVID-19. Among these, recent studies have explored the role of HLA-G molecules and their immunomodulatory effects in COVID-19, but there are very few reports exploring the genetic basis of these manifestations. The present study aims to investigate how host genetic factors, including HLA-G gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection. Materials and Methods: We compared the immune-genetic and phenotypic characteristics between COVID-19 patients (n = 381) with varying degrees of severity of the disease and 420 healthy controls from Sardinia (Italy). Results: HLA-G locus analysis showed that the extended haplotype HLA-G*01:01:01:01/UTR-1 was more prevalent in both COVID-19 patients and controls. In particular, this extended haplotype was more common among patients with mild symptoms than those with severe symptoms [22.7% vs 15.7%, OR = 0.634 (95% CI 0.440 – 0.913); P = 0.016]. Furthermore, the most significant HLA-G 3’UTR polymorphism (rs371194629) shows that the HLA-G 3’UTR Del/Del genotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X2 = 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X2 = 11.257, P = 0.004). However, no significant differences were observed for the soluble HLA-G levels in patients and controls. Finally, we showed that SARS-CoV-2 infection in the Sardinian population is also influenced by other genetic factors such as β-thalassemia trait (rs11549407C&gt;T in the HBB gene), KIR2DS2/HLA-C C1+ group combination and the HLA-B*58:01, C*07:01, DRB1*03:01 haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal LZTFL1 gene variant (rs35044562A&gt;G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model, HLA-G 3’UTR Del/Del genotype was independent from the other significant variables [ORM = 0.4 (95% CI 0.2 – 0.7), PM = 6.5 x 10-4]. Conclusion: Our results reveal novel genetic variants which could potentially serve as biomarkers for disease prognosis and treatment, highlighting the importance of considering genetic factors in the management of COVID-19 patients

The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materialsWe analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). ResultsAnalysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D' = 0.92 vs D' = 0.50 respectively; P = 1.3x10(-8)). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 - 17.4) U/mL vs 21.3 (16.5 - 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 - 44.8) U/mL vs 8.8 (6.1 - 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. ConclusionThis study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1

Haplotype Affinities Resolve a Major Component of Goat (Capra hircus) MtDNA D-Loop Diversity and Reveal Specific Features of the Sardinian Stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity

High Differentiation among Eight Villages in a Secluded Area of Sardinia Revealed by Genome-Wide High Density SNPs Analysis

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not “a priori” be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates