Alu elements within the human major histocompatibility class I region in the Comoros Islands: genetic variation and population relationships

Abstract

Background: Alu elements are attractive markers for population genetics, disease, forensics and paternity analyses, due to their particular characteristics. Five polymorphic Alu insertions within the MHC class I region have been little examined in human populations.

Aim: The analysis of the genetic diversity of autochthonous Comorians from the three major islands of the archipelago by these polymorphic MHC Alus and to assess their relationships together and with other populations.

Subjects and methods: Two hundred and fifty-seven unrelated participants from the Comoros archipelago, Grande Comore (86), Anjouan (93) and Moheli (78), were examined for five MHC Alu insertions. The data were analysed for intra- and inter-population genetic variation.

Results: All MHC Alu were polymorphic in the three samples and only one significant differentiation was observed between Anjouan and Moheli. According to the MDS and AMOVA results, the populations included in the inter-population analyses were grouped in three major clusters according to their genetic ancestry. The haplotype diversity showed by the Comorians is higher than in previously studied African populations and occupies an intermediate position between African and Asian clusters.

Conclusion: MHC Alu insertions are useful markers to study micro-geographical genetic variations. Using these polymorphisms, new insights have been obtained about the biological history and evolution of the Comoros.     

Genetic Change in the Polynesian Population of Easter Island: Evidence from Alu Insertion Polymorphisms

The origin of Pacific islanders is still an open issue in human population genetics. To address this topic we analyzed a set of 18 Alu insertion polymorphisms in a total of 176 chromosomes from native Easter Island inhabitants ( Rapanui ). Available genealogical records allowed us to subdivide the total island sample into two groups, representative of the native population living in the island around 1900, and another formed by individuals with some ancestors of non- Rapanui origin. Significant genetic differentiation was found between these groups, allowing us to make some biodemographic and historical inferences about the origin and evolution of this geographically isolated island population. Our data are consistent with equivalent and recent contributions from Amerindian and European migrants to the 1900s Rapanui population, with an accelerated increase in the European gene flow during the 20^th century, especially since the 1960s. Comparative analysis of our results with other available Alu variation data on neighbouring populations supports the "Voyaging Corridor" model of Polynesian human settlement, which indicates that pre-Polynesians are mainly derived from Southeast Asian and Wallacean populations rather than from Taiwan or the Philippines. This study underlines the importance of sampling and taking into account historical information in genetic studies to unravel the recent evolution of human populations.     

Investigation of the genetic structure of Kabyle and Chaouia Algerian populations through the polymorphism of Alu insertion markers

Abstract

Background: In Algeria, as in all North Africa, Berbers constitute the old background of the population. Today, Berber speakers account for only ～ 25% of Algerians. This decline is the product of a complex human settlement from pre-history to recent invaders.

Aim: This study aims to determine the genetic diversity level within a sample of five Algerian Berber speaking populations in order to contribute to resolving issues about the North African population settlement.

Subjects and methods: Two Algerian Berber groups (Kabyle and Chaouia), originated from five administrative regions from Algeria, were typed for 11 Alu Insertions. Analysis has been based on Fst genetic distance, AMOVA, NMDS and distance to the centroid model.

Results: No genetic differentiation has been observed between all Algerian Berbers discarding any geographical or ethnic effect. Comparative analyses based on Fst genetic distance did not show significant affinities between North Africans and either South Europeans or Middle Easterners, except genetic proximity between Algerians and Iberians. The amount of genetic diversity among Algerians and North African populations detected by the distance to the centroid model was significant compared with other North Mediterranean populations.

Conclusion: A strong genetic homogeneity has been found between Algerian Berbers. Global genetic diversity based on Alu markers is following the isolation by distance model, except for some European populations.     

Butyrylcholinesterase,ApoE and Alzheimer's disease in a population from the Canary Islands (Spain)

Aim: Cholinergic dysfunction is a major neurochemical feature in Alzheimer's disease (AD), accountable for many cognitive dysfunctions and some psychiatric symptoms. Butyrylcholinesterase (BChE) is one of the cholinesterases with increased activity in the brain of Alzheimer's patients. Several mutations code for different BChE, such as the K variant, which is the most common and is capable of reducing BChE activity by 30%. We studied the relationship between this K variant and Alzheimer's disease in our population from the Canary Islands (Spain). Patients and methods: We used DNA PCR-RFLP techniques to compare 282 patients who had been diagnosed with probable Alzheimer's disease – according to NINCS-ADRDA criteria – with 312 control subjects confirmed to be free of cognitive impairment as assessed by using the CAMDEX cognitive subscale CAMCOG. Results: In our population the K variant of BChE is linked to the age of diagnosis of Alzheimer's disease, since AD individuals with this allele presented the disease at a later stage. No other susceptibility relations are exposed in this study. In addition, the BChE allelic frequencies in our population are higher than those previously reported.     

Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily

Apert syndrome (AS) is a severe disorder, characterized by craniosynostosis and complex syndactyly of the hands and feet. Two heterozygous gain-of-function substitutions (Ser252Trp and Pro253Arg) in exon IIIa of fibroblast growth factor receptor 2 (FGFR2) are responsible for >98% of cases. Here we describe two novel mutations in FGFR2 in the two patients in whom a mutation had not previously been found in our cohort of 227 AS cases. The first is a 1.93-kb deletion, removing exon IIIc and substantial portions of the flanking introns. This is the first large FGFR2 deletion described in any individual with craniosynostosis. The other mutation is a 5' truncated Alu insertion into exon IIIc. This is the third Alu insertion identified in AS; all have occurred within an interval of only 104 bp, representing an enrichment of over a million-fold compared to the background genomic rate. We show that the inserted Alu element belongs to a small subfamily, not previously known to be mobile, which we term Alu Yk13. Both the deletion and insertion are likely to act by a similar gain-of-function mechanism in which disruption of exon IIIc leads to illegitimate mesenchymal expression of an FGFR2 spliceform containing the alternatively spliced exon IIIb. All the AS-associated Alu insertions have arisen in the paternal germline; we propose that their enrichment in FGFR2 is driven by positive selection of the mutant spermatogonial progenitors, a mechanism analogous to that explaining why the canonical AS nucleotide substitutions also reach exceptionally high levels in sperm.     

MHC class I polymorphic Alu insertion (POALIN) allele and haplotype frequencies in the Arabs of the United Arab Emirates and other world populations

Polymorphic Alu insertions (POALINs) are found throughout the human genome and have been used in various studies to infer geographic origin of human populations. The main aim of this study was to determine the allele and haplotype frequencies of five POALINs, AluHF, AluHG, AluHJ, AluTF and AluMICB, within the major histocompatibility complex (MHC) class I region of 95 UAE Arabs, and correlate their frequencies to those of the HLA‐A, HLA‐C and HLA‐B class I allele lineages. Evolutionary relationships between the POALINs of the Arabs and those previously studied in populations of African, Asian and European descent were compared. At each of the five Alu loci (AluHF, AluHG, AluHJ, AluTF and AluMICB), Alu insertion was designated as Alu(locus)*02 and absence was Alu(locus)*01. The AluHG insertion (AluHG*02) had the highest frequency (0.332), followed by AluHF*02 (0.300), AluHJ*02 (0.263), AluMICB*02 (0.111) and AluTF*02 (0.058). Of the 270 Alu‐HLA haplotypes pairs in the UAE Arabs, 110 had no Alu insertion, and 54 had an Alu insertion at >50% per haplotype. An Alu insertion >75% per haplotype was found between AluMICB*02 and HLA‐B*14, HLA‐B*22, HLA‐B*44, HLA‐B*55, HLA‐B*57 and HLA‐B*73, and with HLA‐C*01 and HLA‐C*18; AluHJ*02 with HLA‐A*01, HLA‐A*19, HLA‐A*24 and HLA‐A*32; AluHG*02 with HLA‐A*02 and HLA‐B*18; and AluHF*02 with HLA‐A*10. The genotyped allele and haplotype frequencies of the MHC POALINs in UAE Arabs were compared with the results of 30 previously published Asian, European, American and African populations. Phylogenetic and multidimensional scaling (MDS) analysis of the relative MHC POALINs allele and haplotype frequencies revealed that the UAE Arabs have a similar lineage to Caucasians and the most distant genetic relationship to the Waorani native American population of Ecuador. The structure of both the phylogenetic tree and the MDS analysis supports the Out of Africa theory of human evolution. The nature of the clusters suggests the Arabian Middle East represents a crossroads from which human populations migrated towards Asia in the east and Europe to the north‐west.     

New insights into the genetic history of Tunisians: Data from Alu insertion and apolipoprotein E gene polymorphisms

Background: Among polymorphisms of non-transcribed DNA sequences and functional genes, those of Alu insertions and that of the APOE gene have been widely used to clarify the degree of genetic relationships between human populations.

Aim: APOE gene and eight Alu insertion polymorphisms were investigated in Tunisians and compared with data from neighbour populations in order to gain new insights into the genetic position of Tunisia in the Mediterranean region.

Subjects and methods: A total of 121 individuals from the North and Centre-South regions were sampled.

Results: No significant genetic differences were found between Tunisians and North Africans when samples representative of wide areas were considered. APOE gene variation seemed slightly less powerful than the Alu polymorphisms in detecting North–South Mediterranean differences.

Conclusion: North African populations show a substantial degree of genetic homogeneity, which may reflect the similarity of their origins, mainly when samples from large geographical areas are compared. The relative genetic homogeneity of the whole Mediterranean region probably reflects a common origin and/or remarkable levels of gene flow. However, this gene flow has not yet erased the differentiation between the two Mediterranean shores, as revealed by Alu insertion polymorphisms.     

Geographical and social influences on genetic diversity within the Egyptian population: analyses of Alu insertion polymorphisms

Background: The geographical location of Egypt at the crossroads of several major cultural areas between North Africa and the Middle East has contributed to its population history.

Aim: To analyse the genetic structure of the population living in two geographical parts of Egypt.

Subjects and methods: A sample of 112 Egyptians from the North African part of Egypt (Ismailia sample) and a sample of 52 Egyptians from the Asian part Sinai, have been analysed using 10 Alu insertion polymorphisms.

Results: The results of the present study showed a significant genetic difference between the Sinai and Ismailia samples. The latter showed an evident genetic affinity with North African populations; whereas the Sinai sample was found to be genetically closer to the Middle East populations. The Sinai sample showed a low average heterozygosity, unlike that found in the Ismailia sample.

Conclusion: This study provides new insights into the genetic structure of the Egyptian population living in a land bridge between Africa and Asia. Results suggest a genetic discontinuity between the Sinai population and that of the North African part of Egypt. This discontinuity would have been maintained thanks to geo-climatic and social factors.     

Ethnic composition and genetic differentiation of the Libyan population: insights on Alu polymorphisms

Background: It is thought that the ancient population of Libya was mainly composed of Saharan Berbers. Socio-geographic conditions and historical events have exerted some changes on the composition of the present-day Libyan population.

Aim: To screen a set of autosomal Alu markers in a representative sample of the general Libyan population in order to study its ethnic and genetic structure and to re-examine its genetic relationships with Mediterranean and Middle Eastern groups.

Subjects and methods: A sample of 190 Libyans was analysed for 17 Alu insertions. The sample was divided according to the Arabic or Berber origin of individuals’ surnames.

Results: The current general Libyan population is homogeneous and shows considerable genetic diversity compared with other North Mediterranean and North African populations. It shows intermediate genetic distances between Moroccans, Algerians and Tunisians on one side and Egyptian Siwa Berbers on the other. No particular affinities with Middle Eastern groups were detected.

Conclusion: Alu insertions are useful markers to contribute to the reconstruction of human population history at a microgeographic scale, in particular when the analyses include anthropologically well sampled populations. The present results provide new information to improve understanding some aspects of the complex peopling of North Africa.     

Neonatal severe hyperparathyroidism,secondary hyperparathyroidism,and familial hypocalciuric hypercalcemia: Multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene

Neonatal severe hyperparathyroidism (NSHPT) is considered an autosomal-recessive disorder, attributable in many cases to homozygous inactivating mutations of the Ca⁺⁺-sensing receptor (CASR) gene at 3q13.3–21. Most heterozygotes are clinically asymptomatic but manifest as familial (benign) hypocalciuric hypercalcemia (FHH) with a laboratory profile that is variably and sometimes only marginally different from normal. In 5 NSHPT cases from 3 Nova Scotian families, we found homoallelic homozygosity for an insertion mutation in exon 7 of CASR that includes an Alu repeat element with an exceptionally long polyA tract. Four of the 5 NSHPT infants were treated by parathyroidectomy more than a decade ago and are well now. A fifth went undiagnosed until adulthood and has profound musculoskeletal and neurobehavioral deficits. Among 36 identified FHH heterozygotes are 3 individuals with an unexpected degree of hypercalcemia and elevated circulating parathyroid hormone levels consistent with secondary hyperparathyroidism. Two are obligately heterozygous offspring of NSHPT mothers with surgical hypoparathyroidism and variable compliance with vitamin D therapy. The other is an adult with coexistent celiac disease in whom hyperparathyroidism, probably secondary to vitamin D deficiency, led to surgery. In counseling affected families, the heterozygous state should not be considered entirely benign, since FHH heterozygotes, particularly infants, may be prone to secondary hyperparathyroidism and symptomatic hypercalcemia. In such families, molecular diagnosis will allow for unambiguous identification of at-risk individuals. Am. J. Med. Genet. 71:202–210, 1997. © 1997 Wiley-Liss, Inc.     

Polymorphisms of the COL1A2, CYP1A1 and HS1,2 Ig enhancer genes in the Tuaregs from Libya

Background: Restriction fragment length polymorphisms (RFLPs) of the COL1A2 and CYP1A1 and short tandem repeats of HS1,2 Ig enhancer genes are proving to be useful markers for describing human populations and thus are of interest for anthropogenetic research. Moreover, they can provide useful information in identifying alleles and haplotypes associated with particular forms of common diseases or for pharmacogenomics studies.

Aim: The objective of this study was to define the genetic structure of Libyan Tuaregs and to establish the degree of genetic homogeneity amongst the El Awaynat and Tahala groups.

Subjects and methods: Tuareg individuals from El Awaynat (n?=?99) and Tahala (n?=?18), in Libyan Sahara, were analysed for the RFLPs of COL1A2 and CYP1A1 and short tandem repeats of HS1,2 Ig enhancer genes. In order to provide a clearer picture of COL1A2, CYP1A1 and HS1,2 Ig enhancer allele and haplotype frequency distributions in various human groups distributed over a wide geographic area, comparisons with other African, European and Asian populations were carried out by analysis of molecular variance (AMOVA) and genetic distance analysis.

Results: No significant level of differentiation was evident between the two Libyan Tuareg groups according to AMOVA. For the CYP1A1 gene, a possible new haplotype was observed, even though at a very low frequency. Linkage disequilibrium was assessed only for COL1A2, since CYP1A1 turned out to be poorly polymorphic for m2 and m3.

Conclusions: Statistical analyses showed that Tuaregs from Libya are located in a intermediate position between south Saharan populations on one side and the Europeans and the Asians on the other.     

Homogeneous assay of rs4343, an ACE I/D proxy, and an analysis in the British Women's Heart and Health Study (BWHHS)

Current literature suggests that ACE SNP rs4343, ACE 2350A>G in exon 17, T202T, may be the best proxy for the ACE Alu I/D whereas rs4363 and rs4362 may be slightly stronger predictors of ACE levels. Considering reported difficulties in genotyping ACE I/D and stronger associations of rs4343 than ACE I/D with plasma ACE levels in Africans, and suitability of rs4343 for allelic mRNA (cDNA) studies, we developed and validated a liquid phase assay for rs4343, which has advantage on both functional and technical grounds. We confirmed that rs4343, is in near perfect linkage disequilibrium (D'=1, r2=0.88, n=64) with ACE I/D in Europeans (A and G alleles of rs4343 marking insertion and deletion alleles of ACE I/D respectively). We then studied its association with metabolic and cardiovascular traits in 3253 British women (60-79 years old). Apart from a nominal trend of association with diastolic blood pressure (p anova=0.08; p trend=0.05), no other associations were observed. A post-hoc vascular and general phenome scan revealed no further associations. We conclude that ACE I/D is not a major determinant of metabolic and cardiovascular traits in this population. Liquid phase genotyping of SNP rs4343 may be preferable to gel based ACE I/D genotyping both for technical and functional reasons.     

Non-homologous recombination between Alu and LINE-1 repeats caused a 430-kb deletion in the dystrophin gene: a novel source of genomic instability

Although large deletions in the dystrophin gene have been identified in more than two-thirds of Duchenne and Becker muscular dystrophy patients, the molecular mechanisms that lead to the generation of these deletions are largely unknown. Here, Alu and LINE-1 (L1) repetitive elements were shown to be present at one or other of the two ends, respectively, of a 430-kb deletion in the dystrophin gene. The breakpoint of the deletion, which stretches from exons 2 to 7, was defined more precisely by polymerase chain reaction (PCR) walking on introns 1 and 7. Finally, the region containing the breakpoint was amplified as a fragment of more than 10 kb. Sequencing of the deletion endpoint revealed the presence of an Alu sequence in intron 1, 25 kb downstream from the 3′ end of exon 1 that was joined directly to an L1 sequence in intron 7, 4.5 kb downstream from the 3′ end of exon 7. The deletion was calculated to be 430 kb. To our knowledge, this is a novel recombination event joining non-homologous Alu and L1 repeats, and is the largest known intrachromosomal deletion that is thought to involve repetitive genetic elements. Sequence characteristics around the breakpoint are discussed. Received: July 10, 2000 / Accepted: August 23, 2000     

Polymorphisms at the Werner locus: I. Newly identified polymorphisms,ethnic variability of 1367Cy/Arg,and its stability in a population of Finnish centenarians

The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutations, all of which result in the truncation of the protein, lead to Werner syndrome. However, little is known about the role of WRN in “normal” aging. We have identified four missense polymorphisms and four conservative polymorphsims in WRN gene. A single study showed that a polymorphism at amino acid 1367 Cys(TTG)/Arg(CTG) is associated with a variation in risk of myocardial infarction among a Japanese population. The 1367 Cys/Arg polymorphism was examined during aging in three different populations: Finnish, Mexican, and North American. The frequencies of 1367 Cys were higher than those of 1367 Arg in all the populations examined, though the frequencies varied among populations. The frequency of the 1367 Arg allele, thought to be protective against myocardial infarction in a Japanese population, was approximately three times higher in the North American and Finnish adult populations. When newborns and centenarians were compared within the Finnish population, no differences were observed in the proportions of 1367 Cys/Arg across age groups. Within the Finnish population, we confirmed a significant decrease of the APOE ϵ2 allele and an increase in the ϵ4 allele in newborn infants compared with centenarians. Thus, unlike the APOE polymorphism, there is no evidence of an association of this WRN polymorphism with longevity. Am. J. Med. Genet. 82:399–403, 1999. © 1999 Wiley-Liss, Inc.     

Anxiety,Symptoms and Containment: A Tale of Two Situations

In this paper the author considers the relationship between anxiety, symptoms and containment. She notes that the securest of us feel what we can call mature anxiety. Physically, it is different from immature, pathological anxiety where development of a part or parts of the self has been arrested. Immature, pathological anxiety, which is encountered and treated in the consulting room, brings with it the bodily upset that is seen in anxiety. In the author's experience what we struggle with nowadays is far more likely to be variants of what we have come rather vaguely to call personality disorder. In this situation the anxiety, though intense, is diffused through the self, finding its fateful and addictive manifestations in relationships and their failure, identity problems, inability to work and the sequelae of that, pathological indecision, rage and a general, miserable dissatisfaction with life and what it offers. But anxiety remains central all the time. To provide a frame for some of these thoughts, the author considers Dickens's A Tale of Two Cities. The character of Dr Manette provides an example of the symptomatic personality, and the character of Sidney Carton of the much more modern, personality‐disordered individual.     

阿尔茨海默病精神症状与载脂蛋白E基因多态性相关性研究

目的探讨载脂蛋白E基因与中国昆明地区汉族人阿尔茨海默病精神症状是否存在关联。方法运用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析方法,对58例无亲缘关系的中国昆明地区阿尔茨海默病患者及96例健康老年人,进行载脂蛋白E基因变异检测;采用神经精神量表(Neuropsychiatric Inventory Caregiver Distress Scale,NPI)评定患者的精神症状。结果AD组ε3/ε4基因型频率及ε4等位基因频率明显高于对照组(P<0.05);发现有妄想、抑郁心境、攻击行为症状组的ε4/x基因型频率及ε4等位基因频率高于无症状组,有幻觉症状组的ε4/x基因型频率及ε4等位基因频率低于无症状组,差异比较经χ2检验,均无统计学意义。结论ε4基因可能是AD的风险基因;ApoEε4等位基因与AD精神症状的发生并无关联。