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Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue. It presents with a wide spectrum of skeletal and extraskeletal features, and ranges in severity from mild to perinatal lethal. The disease is characterized by a heterogeneous genetic background, where approximately 85%-90% of cases have dominantly inherited heterozygous pathogenic variants located in the COL1A1 and COL1A2 genes. This paper presents the results of the first nationwide study, performed on a large cohort of 197 Polish OI patients. Variants were identified using a next-generation sequencing (NGS) custom gene panel and multiplex ligation probe amplification (MLPA) assay. The following OI types were observed: 1 (42%), 2 (3%), 3 (35%), and 4 (20%). Collagen type I pathogenic variants were reported in 108 families. Alterations were observed in a1 and a2 in 70% and 30% of cases, respectively. The presented paper reports 97 distinct causative variants and expands the OI database with 38 novel pathogenic changes. It also enabled the identification of the first glycine- to-tryptophan substitution in the COL1A1 gene and brought new insights into the clinical severity associated with variants localized in "lethal regions". Our results contribute to a better understanding of the clinical and genetic aspects of OI. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) is a novel star factor in the research of ocular diseases including cataract and the most common postoperative complication posterior capsule opacification (PCO). Hsa_circRNA_0060640 (circ_0060640) is an age-related cataract-related circRNA. However, its role in cataractogenesis is unrevealed yet. PCO in vitro model was established in human lens epithelium cells (hLECs) induced by transforming growth factor-beta2 (TGF-β2). RNA and protein expressions were respectively detected by quantitative PCR and western blotting. Direct interaction between two RNAs was predicted by Starbase tool and confirmed by dual-luciferase reporter assay. MTS and EdU assays measured cell proliferation; Transwell, starch wound and western blotting assays evaluated cell motility and epithelial-mesenchymal transition (EMT). Circ_0060640 expression is higher in anterior lens capsule tissues from human cataractous eyes and TGF-β2-stimulated hLECs cells line SRA01/04. RNA interference of circ_0060640 could prevent SRA01/04 cells from TGF-β2-induced cell proliferation, migration and invasion, accompanied with decreased N-cadherin and α-smooth muscle actin and increased E-cadherin. Mechanistically, circ_0060640 directly controls microRNA (miR)-214-3p expression and then regulates gene expression of collagen type I alpha2 chain (COL1A2). Notably, COL1A2 inhibition is underlying the protective role of circ_0060640 silencing and miR-214-3p ectopic expression in TGF-β2-stimulated SRA01/04 cells. Circ_0060640 is a novel cataract-related gene and its silencing could block TGF-β2-evoked hLECs proliferation, motility and EMT in vitro via targeting miR-214-3p-COL1A2 axis. Therefore, targeting circ_0060640 via RNA interference might be a treatment strategy for PCO development. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a rare inherited connective tissue dysplasia characterized with skeletal fragility, recurrent fractures and bone deformity, predominantly caused by mutations in the genes COL1A1 or COL1A2 that encode the chains of type I collagen. In the present study, clinical manifestations and genetic variants were analysed from 187 Chinese OI patients, majority of whom are of southern Chinese origin. By targeted sequencing, 63 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 8 novel COL1A1 and 7 novel COL1A2 variants. We validated a novel splicing mutation in COL1A1. A diverse mutational and phenotypic spectrum was observed, coupling with the heterogeneity observed in the transcriptomic data derived from osteoblasts of six patients from our cohort. Missense mutations were significantly associated (χ2 p = 0.0096) with a cluster of patients with more severe clinical phenotypes. Additionally, the severity of OI was more correlated with the quality of bones, rather than the bone mineral density. Bone density is most responsive to bisphosphonate treatment during the juvenile stage (10–15 years old). In contrast, height is not responsive to bisphosphonate treatment. Our findings expand the mutational spectrum of type I collagen genes and the genotype-phenotype correlation in Chinese OI patients. The observation of effective bisphosphonate treatment in an age-specific manner may help to improve OI patient management. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a rare genetic disorder demonstrating considerable phenotypic and genetic heterogeneity. The extensively studied genotype–phenotype correlation is a crucial issue for a reliable counseling, as the disease is recognized at increasingly earlier stages of life, including prenatal period. Based on population studies, clusters in COL1A1 and COL1A2 genes associated with the presence of glycine substitutions leading to fatal outcome have been distinguished and named as "lethal regions." Their localization corresponds to the ligand-binding sites responsible for extracellular interactions of collagen molecules, which could explain high mortality associated with mutations mapping to these regions. Although a number of non-lethal cases have been identified from the variants located in lethal clusters, the mortality rate of mutations has not been updated. An next generation sequencing analysis, using a custom gene panel of known and candidate OI genes, was performed on a group of 166 OI patients and revealed seven individuals with a causative mutations located in the lethal regions. Patients' age, ranging between 3 and 25 years, excluded the expected fatal outcome. The identification of non-lethal cases caused by mutations located in lethal domains prompted us to determine the actual mortality caused by glycine substitutions mapping to lethal clusters and evaluate the distribution of all lethal glycine mutations across collagen type I genes, based on records deposited in the OI Variant Database. Finally, we identified six glycine substitutions located in lethal regions of COL1A1 and COL1A2 genes, of which four are novel. The review of all mutations in the dedicated OI database, revealed 33 distinct glycine substitutions in two lethal domains of COL1A1 , 26 of which have been associated with a fatal outcome. Similarly, 109 glycine substitutions have been identified in eight lethal clusters of COL1A2 , of which 51 have been associated with a fatal manifestation. An analysis of all glycine substitutions leading to fatal phenotype, showed that their distribution along collagen type I genes is not regular, with 17% (26 out of 154) of mutations reported in COL1A1 and 64% (51 out of 80) in COL1A2 corresponding to localization of the lethal regions. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) describes the unexpected natural death from a cardiac cause within a short time period. Compelling evidence suggests the involvement of host genetic factors in SCD etiology. Identification of genetic variations predisposed to SCD enables genetic testing that may contribute to SCD diagnosis and risk stratification. Previous studies have suggested that dysregulation of pro-alpha2 chain of type I collagen, encoded by collagen type I alpha 2 chain ( COL1A2 ) gene, was involved in cardiac disorders such as myocardial infarction, hypertrophic cardiomyopathy and atherosclerosis. By using a candidate-gene-based approach, we evaluated the association of a 7-base pair (7-bp) indel polymorphism (rs3917) in the 3′UTR of COL1A2 with the risk of SCD in a Chinese population (79 SCD cases and 328 controls). Logistic regression analysis showed that the deletion allele of rs3917 significantly increased the risk of SCD [odds ratio (OR) = 1.82; 95% confidence interval (CI) = 1.08–3.06; P = 0.0159]. Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with lower expression of COL1A2 in human myocardium tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that rs3917 could regulate COL1A2 expression through interrupting the binding of miR-296-3p with COL1A2 in an allele-dependent manner, which in turn confer SCD risk. Our data provided initial evidence that rs3917 was highly relevant to SCD susceptibility, and this indel may become a potential marker for molecular diagnosis and genetic counseling of SCD. The replication of our studies and further functional studies are needed to validate our findings. [ABSTRACT FROM AUTHOR]

This study explored the mechanism underlying the stimulation of collagen synthesis and osteoblastic differentiation by insulin-like growth factor 1 (IGF1) in primary mouse osteoblasts. Primary mouse calvarial osteoblasts were cultured and treated with various doses of IGF1 before transfection with siRNA targeting the collagen type I alpha 2 (Col1a2) or La ribonucleoprotein domain family member 6 (Larp6) genes. Alkaline phosphatase (ALP) activity, osteocalcin staining, alizarin red quantification and the expression level of runt-related transcription factor 2 (RUNX2) were performed to assess the differentiation of pre-osteoblasts. Based on Western blot analysis, IGF1 up-regulated COL1A2 protein expression in the primary osteoblasts in a dose- and time-dependent manner. In addition, Col1a2 interference inhibited the differentiation and mineralization of osteoblasts. IGF1 also stimulated the differentiation of mouse primary osteoblasts and increased LARP6 expression during osteogenic differentiation. RNA-Immunoprecipitation (IP) indicated that LARP6 could bind to Col1a2 mRNA after IGF1 stimulation. However, transfection of Larp6-specific siRNA significantly reduced collagen and ALP secretion, mineralization and inhibited the expression of osteocalcin and RUNX2, indicating that Larp6 interference inhibited the differentiation ability of primary mouse calvarial osteoblasts, and these effects could not be reversed by IGF1. Thus, IGF1 could promote COL1A2 expression and osteoblast differentiation in primary mouse calvarial preosteoblasts by increasing LARP6 expression via a posttranscriptional mechanism. [ABSTRACT FROM AUTHOR]

Background/Aims: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis. Methods: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared. Results: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC. Conclusion: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis. [ABSTRACT FROM AUTHOR]

Background: The role of type I collagen, composed of collagen type I alpha 1 (COL1A1) and collagen type I alpha 2 (COL1A2), has been studied in several cancers. However, the expression of COL1A1 and COL1A2 in malignant, premalignant, and normal gastric tissues and their clinical significances in gastric cancer have not been elucidated. Methods: Real-time quantitative PCR was performed in 55 malignant, 27 premalignant, and 19 normal tissues to measure COL1A1 and COL1A2 messenger RNA (mRNA) expression, and the correlations between COL1A1 and COL1A2 expression and clinicopathological parameters and patients' survival rate were analyzed. Results: We found that COL1A1 mRNA expression was significantly upregulated in premalignant and malignant tissues than in normal tissues, whereas COL1A2 mRNA expression was significantly higher in malignant tissues than in premalignant and normal tissues. Moreover, COL1A1 expression was unrelated to clinicopathological parameters, while COL1A2 expression was positively related to tumor size and depth of invasion. Besides, higher COL1A1 and COL1A2 expression levels were related to lower overall survival. Conclusions: We find that COL1A1 might have its potential as a monitoring factor to screen early gastric cancer, and COL1A1 and COL1A2 might predict poor clinical outcomes in gastric cancer patients. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to evaluate the putative association between the presence of the COL1A2 gene A/C polymorphism and the severity of dental fluorosis in a sample exposed to high concentrations of fluoride. Methods A cross-sectional study was carried out that included 80 children residing in a community with high concentrations of fluoride in the drinking water. To determine whether the presence of this polymorphism and dental fluorosis are associated, the presence of the dental fluorosis was considered to be a response variable, while fluoride concentration in water and urine was designated as independent variables. In addition, the children's parents completed questionnaires with general information about drinking and cooking with tap water, consumption of milk and soft drinks, and other putative risk factors. Results Individuals with the polymorphism had nonsignificant odds ( OR = 2.24; 95% CI = 0.55-9.02) of having dental fluorosis at higher exposures to fluoride. This finding was similar in individuals without the polymorphism ( OR = 1.65; 95% CI = 0.44-6.17). Conclusions The presence of polymorphism in the COL1A2 gene was not associated with the severity of dental fluorosis. [ABSTRACT FROM AUTHOR]

The term of osteogenesis imperfecta (OI) includes a heterogeneous group of genetic disorders of connective tissue and has as the main form of expression recurrent fractures, skeletal fragility and deformity. OI is one of the most common skeletal dysplasias. The disease has an etiology related directly or indirectly to type I collagen, the most important protein of the bone extracellular matrix. The diagnosis of OI is based on history and clinical examination associated with genetic analyses, imaging and laboratory investigations. OI is a disorder which has many clinical manifestations, some of these are present only in certain types of the disease, some characteristics being agedependent. There is no cure for OI. Treatment is aimed at increasing bone strenght to prevent fracture, the surgical correction of deformity, minimizing pain and maximizing mobility and independent function. [ABSTRACT FROM AUTHOR]

Osteosarcoma, which is the most common type of highly malignant bone tumor in children and adolescents, has poor diagnosis and 2-year survival rates of 15-20% following surgery or radiotherapy, and has therefore generated marked attention. In order to investigate the potential biomarkers for diagnosing osteosarcoma, the expression profiling data from normal and disease tissues were compared, respectively, and the differentially-expressed genes were analyzed by three different statistical tests. Interacting proteins were determined and an interaction network was constructed by Search Tool for the Retrieval of Interacting Genes database. Subsequently, the protein interaction network was decomposed and Gene Otology annotation using Cytoscape, Mcode and Bingo, was conducted on the function modules. Finally, three differentially-expressed genes GJA1, COL1A2 and COL5A2 were identified, and an interaction network was successfully generated with COL1A2 and COL5A2 at the core. From the results, it was observed that COL1A2 and COL5A2 interact with a number of genes of the matrix metalloprotease (MMP) family, including MMP1, MMP2, MMP3 and MMP14, TGFβ and RUNX2. Furthermore, these genes have been confirmed to be important in the tumorigenesis of osteosarcoma. It was hypothesized that the upregulation of the COL gene family may be considered as a diagnostic marker for osteosarcoma and collagen may be administered as a therapy. [ABSTRACT FROM AUTHOR]

Abstract: Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype–phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype–phenotype correlation in genetic counselling in OI. [Copyright &y& Elsevier]

Objectives: Collagen production plays a role in the development of tumors from cancer cells. The aim of the present study is to examine the involvement of epigenetic alteration of Collagen α2 (I) (COL1A2) gene expression in cases of head and neck squamous cell carcinoma (HNSCC). Methods: COL1A2 expression was examined in a panel of cell lines using RT-PCR. The methylation status of the COL1A2 promoter was studied using bisulfate sequencing and methylation-specific PCR (MSP). Results: COL1A2 expression was absent in 6 of 11 (54.5%) UM-SCC cell lines, whereas three nonmalignant cell lines had stable expressions. MSP analysis showed that 46/98 (46.9%) contained methylated alleles. COL1A2 methylation was significantly correlated with tumor size (P=0.041), lymph node status ($P=$ 0.008), tumor stage (P=0.011), H-cadherin} methylation (P=0.039) and disease-free survival (P=0.005). On multivariate Cox proportional hazard regression, which included age, sex, smoking status, and alcohol exposure, both tumor stage and COL1A2 methylation remained independent prognostic factors. Conclusions: This study suggests that CpG hypermethylation is a likely mechanism of COL1A2 gene inactivation, supporting the hypothesis that the COL1A2 gene may play a role in the tumorigenesis of HNSCC and may serve as an important biomarker. [ABSTRACT FROM AUTHOR]

Abstract: Accumulation of type I collagen is a key event in renal interstitial fibrosis. As there is no effective treatment, understanding the site where collagen is transcribed and the factors driving it in response to disease in vivo is critical for designing future therapies. The present research investigated the transcriptional activity of the COL1A2 gene in a mouse model of progressive fibrosis induced by aristolochic acid (aristolochic acid nephropathy, AAN). To achieve this we genetically modified mice to express a reporter gene (LacZ) and CCN2 (connective tissue growth factor) under the transcriptional control of the COL1A2 promoter /enhancer sequences. Using these mice we asked where is collagen actively transcribed and secondly, what is the role of CCN2 in AAN. Here, we report that de-novo transcription of the COL1A2 gene occurred predominantly in damaged tubular epithelial cells during progressive interstitial fibrosis in vivo. The activation of COL1A2 was studied by detection of the reporter gene LacZ and COL1A2 mRNA in interstitial, glomerular, vascular, and tubular epithelial tissue from laser capture microscopy. We also demonstrated that LacZ-positive cells co-express E-Cadherin a marker of epithelial origin which is consistent with an epithelial phenotype which is capable of collagen expression during injury. There was no evidence of detachment of these cells from tubules to become myofibroblasts. Moreover, we showed that the transgenic mice show a modest enhancement of CCN2 expression; however fibrosis induced by AA is the same in transgenics and controls suggesting that CCN2, at this level of expression, is not sufficient to enhance fibrogenesis. Overall our study provides a better understanding into the expression patterns and roles of two major extracellular matrix proteins: type I collagen and CCN2. [Copyright &y& Elsevier]

Hepatocellular carcinoma (HCC) is one of the most common and severe diseases in the world. Besides the influence of environmental factors, such as viral infection, an increasing number of novel genetic components identified by genome-wide association studies have been associated with predisposition to HCC. Thus, studies focusing on functional variants in these findings are indispensable. In the present study, based on in-silico analysis, we carried out a case-control study in a Chinese population (207 cases and 245 controls) to investigate the association between HCC susceptibility with a 7 base pair (bp) insertion/deletion polymorphism (rs3917) in the 3′UTR of COL1A2. Our results showed that the ins/del + del/del genotype had an odds ratio of 1.76 (95% C.I.=1.03–3.01; P=0.028) for developing HCC compared to the ins/ins genotype. Carriers for the “del” allele of rs3917 were associated with a 1.73-fold increased risk for HCC (95% C.I.=1.06–2.84; P trend=0.02). Computational modeling suggests that this polymorphism is located in the hsa-let-7g potential target sequence in the COL1A2 3′ untranslated region. Our data suggest that most likely, common genetic changes in COL1A2 may influence HCC risk, at least in part by let-7g–mediated regulation, which is possibly involved in the pathogenesis of HCC. The replication of our studies in other populations will further strengthen our understanding of this association. [Copyright &y& Elsevier]

Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the α1 or the α2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of α1(I) (n=67) or α2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in α2(I) (n=40), patients with serine substitutions in α1(I) (n=42) on average were shorter (median height z-score −6.0 vs −3.4; P=0.005), indicating that α1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the α2(I) chain but not in the α1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients. [ABSTRACT FROM AUTHOR]

Abstract: Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n =2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P<0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively. [Copyright &y& Elsevier]

Abstract: Collagens are members of one of the most important families of structural proteins in higher organisms. There are 28 types of collagens encoded by 43 genes in humans that fall into several different functional protein classes. Mutations in the major fibrillar collagen genes lead to osteogenesis imperfecta (COL1A1 and COL1A2 encoding the chains of Type I collagen), chondrodysplasias (COL2A1 encoding the chains of Type II collagen), and vascular Ehlers–Danlos syndrome (COL3A1 encoding the chains of Type III collagen). Over the past 2 decades, mutations in these collagen genes have been catalogued, in hopes of understanding the molecular etiology of diseases caused by these mutations, characterizing the genotype–phenotype relationships, and developing robust models predicting the molecular and clinical outcomes. To achieve these goals better, it is necessary to understand the natural patterns of variation in collagen genes in human populations. We screened exons, flanking intronic regions, and conserved noncoding regions for variations in COL1A1, COL1A2, COL2A1, and COL3A1 in 48 individuals from each of four ethnically diverse populations. We identified 459 single-nucleotide polymorphisms (SNPs), more than half of which were novel and not found in public databases. Of the 52 SNPs found in coding regions, 15 caused amino acid substitutions while 37 did not. Although the four collagens have similar gene and protein structures, they have different molecular evolutionary characteristics. For example, COL1A1 appears to have been under substantially stronger negative selection than the rest. Phylogenetic analysis also suggests that the four genes have very different evolutionary histories among the different ethnic groups. Our observations suggest that the study of collagen mutations and their relationships with disease phenotypes should be performed in the context of the genetic background of the subjects. [Copyright &y& Elsevier]

We have previously identified transcription factors binding to the proximal promoter region of the human COL1A2 gene that are essential for promoter activity. Two regions in the proximal promoter, the CCAAT-element and the CME bind the CCAAT-binding factor and an as yet uncharacterized DNA-binding protein, respectively. In this study we show that phosphorylation of both the CCAAT-binding and CME-binding proteins are essential for DNA-binding activity. While the binding of the CCAAT-binding proteins to the COL1A2 proximal promoter was inhibited after treatment of nuclear proteins with calf intestinal phosphatase, PP2A treatment had a significant inhibitory effect on the binding of the CME-binding proteins. The treatment of type I collagen producing fibroblasts, CT-1, with the kinase inhibitor, staurosporine, interfered with DNA-protein interactions on both elements on the COL1A2 proximal promoter. This inhibition was associated with a significant decrease in both endogenous COL1A2 gene expression as observed by northern blot analysis and proximal promoter activity as assayed in transient transfection assays. Our results suggest that the phosphorylation of transcription factors interacting with the COL1A2 proximal promoter is essential for both DNA binding and for the expression of this gene. iubmb Life , 58: 97 – 102, 2006 [ABSTRACT FROM AUTHOR]

Background : Eco RI, Msp I and Rsa I restriction fragment length polymorphisms (RFLPs) of the COL1A2 (type I collagen) gene are proving to be extremely informative markers for describing human populations; therefore they hold considerable potential for anthropogenetic research. Aim : The objective of this study was to characterize at the DNA level the Colorado Indians from Ecuador, for whom only blood group frequency information is available, and to investigate their relationships with the Cayapa—another Ecuadoran Native American group belonging to the same linguistic affiliation—and other world populations. Subjects and methods : Colorado Indians ( n &ThickSpace;=&ThickSpace;80) were analysed for the three anthropologically informative RFLPs of the COL1A2 gene. To better define the genetic relationship between this group and other populations, principal component analysis (PCA) was performed and genetic distances were estimated. Population genetic structure was tested through analysis of molecular variance (AMOVA) by comparing haplotype frequencies. Results : COL1A2 allele and haplotype frequencies showed a certain degree of heterogeneity between the two Chibchan populations of Ecuador. The AMOVA test detected a significant level of differentiation (Fst&ThickSpace;=&ThickSpace;0.034, p &ThickSpace;=&ThickSpace;0.0049) between Colorado and Cayapa Indians. PC and genetic distance analyses showed a clear-cut separation between African and non-African populations; within the latter, the two Native American groups were differentiated from each other. Conclusions : The present findings suggest the presence of a low level of genetic relatedness between the Colorado and the Cayapa, despite their supposed common ethnogenesis. This confirms what has been inferred from other genetic data about the high degree of heterogeneity among Native Americans, even within the same linguistic branch, thus supporting the existence of genetic sub-structure within the central and southern American populations. ..LAN-FR Arrière plan: Les polymorphismes de longueurs de fragments de restriction (RFLP) du gène COL1A2 (collagène de type 1) apparaissent comme des marqueurs humains extrêmement informatifs; ils présentent donc un intérêt potentiel considérable pour les recherches d’anthropogénétique. But: Cette étude caractérise le niveau d’ADN des indiens Colorado de l’Equateur, pour lesquels est seulement disponible l’information sur les fréquences des groupes sanguins, et examine leur relation avec un autre groupe amérindien d’Equateur de même affiliation linguistique, les indiens Cayapa, ainsi qu’avec d’autres populations. Sujets et méthodes: 80 indiens Colorado ont été analysés par rapport aux trois RFLP du gène COL1A2 anthropologiquement informatifs. Afin de mieux définir les relations génétiques de ce groupe avec d’autres populations, on a effectué une analyse en composantes principales et estimé des distances génétiques. La structure génétique de la population a été éprouvée par analyse de variance moléculaire (AMOVA) en comparant les fréquences haplotypiques. Résultats: L’allèle COLA12 et les fréquences haplotypiques indiquent un certain degré d’hétérogénéité des deux populations Chibchan d’Equateur. Le test AMOVA détecte un niveau significatif de différenciation (Fst&ThickSpace;=&ThickSpace;0,034 p &ThickSpace;=&ThickSpace;0.0049) entre indiens Colorado et Cayapa. Les analyses de CP et de distances génétiques montrent une séparation nette entre populations africaines et non africaines. Parmi ces dernières, les deux groupes amérindiens se séparent l’un de l’autre. Conclusion: Ces résultats suggèrent une relation génétique faible entre Colorado et Cayapa, en dépit de leur ethnogenèse supposée commune. Ils confirment ce qui a été inféré à partir d’autres données génétiques, concernant le haut degré d’hétérogénéité des amérindiens, même au sein d’une même branche linguistique, ce qui soutient l’hypothèse de l’existence d’une sous structure génétique dans les populations amérindiennes du centre et du sud des continents américains. [ABSTRACT FROM AUTHOR]

Restriction fragment length polymorphisms are good anthropological markers for discriminating geographically distinct populations at both the allele and the haplotype level. Two communities of African ancestry and ladinos, mestizos, and mulattoes living in the Esmeraldas province in northwestern Ecuador were analyzed for three RFLPs (EcoRI, RsaI. and MspI) of the COL1A2 gene. Also, the same markers were studied in a population sample from Spain to compare the allele and haplotype frequencies of the Esmeraldas populations with those of their representative European pa rental population. Data for the native American and sub Saharan African founder components were available from the literature. No significant levels of differentiation between the two African Ecuadoran communities emerged from either the frequency analysis of each single marker and all three RFLP markers together or from the AMOVA. The ladinos and mestizos also showed a rather similar distribution of allele and haplotype frequencies, confirming that the two ethnic terms do not correspond to genetically different populations. The comparison with the supposed founding European, sub Saharan African, and native American populations indicated a large presence of African genes in the gene pool of both communities, with a higher proportion of the Amerindian component in Viche than in Rio Cayapas. The present findings confirm the previous genetic admixture estimates based on nuclear and mitochondrial DNA markers and the demographic data. [ABSTRACT FROM AUTHOR]