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Human-specific insertion/deletion polymorphisms in Indian populations and their possible evolutionary implications.

DNA samples from 396 unrelated individuals belonging to 14 ethnic populations of India, inhabiting various geographical locations and occupying various positions in the socio-cultural hierarchy, were analysed in respect of 8 human-specific polymorphic insertion/deletion loci. All loci, except Alu CD4, were found to be highly polymorphic in all populations. The levels of average heterozygosities were found to be very high in all populations and, in most populations, also higher than those predicted by the island model of population structure. The coefficient of gene differentiation among Indian populations was found to be higher than populations in most other global regions, except Africa. These results are discussed in the light of two possible scenarios of evolution of Indian populations in the broader context of human evolution.

Alleles↗
PubMed1999

Alu-splice cloning of human Intersectin (ITSN), a putative multivalent binding protein expressed in proliferating and differentiating neurons and overexpressed in Down syndrome.

By Alu-splice PCR we have trapped two exons and subsequently identified the full length cDNA of a human gene, Intersectin (ITSN), which maps to chromosome 21q22.1 between markers D21S320 and D21S325. The gene has the potential to code for at least two different protein isoforms by alternative splicing (ITSN-L and ITSN-S). Intersectin exists with a high degree of similarity in flies, frogs and mammals, suggesting a conserved role in higher eukaryotes. Analysis of the expression pattern of human and mouse Intersectin detected mRNAs in all adult and foetal tissues tested, with the longer isoform present in brain. In situ hybridisation studies in the developing mouse brain showed ITSN expression in both proliferating and differentiating neurons. The genomic structure of ITSN was determined using the chromosome 21 sequences deposited in the public databases. The protein contains several known motifs which implicate ITSN in clathrin mediated endocytosis and synaptic vesicle recycling. The expression pattern of Intersectin in mouse brain, its presumed function and its overexpression in brains from Down syndrome patients, suggest that Intersectin may contribute in a gene dosage-dependent manner to some of the abnormalities of Down syndrome.

Adaptor Proteins, Vesicular Transport↗
PubMed2000

Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?

Mutations in the presenilin-1 (PS-1) gene have been shown to cause early onset Alzheimer's disease (EOAD) in an autosomal dominant manner. We have identified a novel 4.6-kb genomic deletion in the PS-1 gene in a Finnish EOAD family, which leads to an inframe exclusion of exon9 (delta9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the delta9 splice-site mutations. In this present EOAD family, the clinical and neuropathological phenotype of patients are those of the typical AD without indications of spastic paraparesis or 'cotton wool' plaques, which are the hallmarks of the variant AD. A sequence analysis of the deletion crossover site of the mutant and corresponding wild type regions revealed complete homology with the recombigenic 26 bp Alu core sequence at intron 8. In addition, a segment at the intron 9 breakpoint displayed homology with the core sequence, but comparison of the 5' and 3' breakpoint sequences did not reveal significant identity favouring involvement of Alu core sequence-stimulated non-homologous recombination rather than Alu-mediated homologous pairing of the fragments. This study shows that large genomic rearrangements can affect the EOAD gene PS-1 through a mechanism, which may involve Alu core sequence-stimulated recombination.

Age of Onset↗
PubMed2000

MtDNA and Y chromosome polymorphisms in Hungary: inferences from the palaeolithic, neolithic and Uralic influences on the modern Hungarian gene pool.

Magyars imposed their language on Hungarians but seem not to have affected their genetic structure. To better investigate this point, we analysed some mtDNA and Y chromosome polymorphisms in a sample of the Hungarian Palóc who, for historical reasons, could have retained genetic traces of Magyars more than other groups. In addition, we examined a mixed sample from Budapest. About 100 individuals were tested for the markers defining all the European and Asian mtDNA haplogroups and about 50 individuals for some Y chromosome markers, namely the 12f2 and 49a,f/TaqI RFLPs, the YAP insertion, the microsatellites YCAIIa, YCAIIb, DYS19 and the Asian 50f2/C deletion. In the mtDNA analysis only two subjects belonged to the Asian B and M haplogroups. The Y chromosome analyses showed that the Palóc differed from the Budapest sample by the absence of YAP+ allele and by the DYS19 allele distribution; that the proto-European 49a,f Ht 15 and the neolithic 12f2-8Kb were rather uncommon in both groups; that there is a high prevalence of the 49a,f Ht 11 and the YCAII a5-b1; and that the Asian 50f2/C deletion is absent. These results suggest that the influence of Magyars on the Hungarian gene pool has been very low through both females and males and the Hungarian language could be an example of cultural dominance. Alternative explanations are discussed. An expansion centred on YAP-, 49a,f Ht 11 is revealed by the median network based on compound haplotypes. 49a,f Ht 11 could represent either a paleolithic marker of eastern Europe which underwent expansion after the last glacial period, or a marker of the more recent spread of the Yamnaia culture from southern Ukraine.

Alu Elements↗
PubMed2001

Alu insertion polymorphisms and the genetic structure of human populations from the Caucasus.

An analysis of 8 Alu insertion loci (ACE, TPA25, PV92, APO, FXIIIB, D1, A25, B65) has been carried out in six populations from the Caucasus, including Indo-European-speaking Armenians; Altaic-speaking Azerbaijanians; North Caucasian-speaking Cherkessians, Darginians, and Ingushians; and South Caucasian (Kartvelian)-speaking Georgians. The Caucasus populations exhibit low levels of within-population variation and high levels of between-population differentiation, with the average Fst value for the Caucasus of 0.113, which is almost as large as the Fst value of 0.157 for worldwide populations. Maximum likelihood tree and principal coordinate analyses both group the Caucasus populations with European populations. Neither geographic nor linguistic relationships appear to explain the genetic relationships of Caucasus populations. Instead, it appears as if they have been small and relatively isolated, and hence genetic drift has been the dominant influence on the genetic structure of Caucasus populations.

Alleles↗
PubMed2004

Unbalanced segregation of a complex four-break 5q23-31 insertion in the 5p13 band in a malformed child.

A rec(5)dup(5)(q23.2q31.3) inherited from a maternal ins(5)(p13.1q23.2q31.3) was detected in a 4-month-old male child who showed hypotonia, microcephaly, cardiac defects, pulmonary hypoplasia and stenosis, bilateral hydronephrosis, hydrocele, testicular hypoplasia and phimosis. Dysmorphisms were also observed. We compare the clinical characteristics of our patient with those of the previously reported dup5q cases in an attempt to define the phenotype-karyotype correlation. The maternal insertion responsible for the duplicated 5q23.2-31.3 region in the child was characterized in detail by FISH analysis, which identified a complex rearrangement involving four breakpoints (bkp's): a 5q segment excised following breakage at 5q23.2 and 5q31.3 became inverted and inserted at 5p13.1, probably coincidentally with an internal breakage at 5q23.3 causing a 180 degrees rotation of the two subsegments. The mother's karyotype was consequently defined as 46,XX, ins(5)(pter --> p13.1 Colon, two colons q23.3 --> q23.2 Colon, two colons q31.3 --> q23.3 Colon, two colons p13.1 --> q23.2 Colon, two colons q31.3 --> qter). There are clusters of Alu sequences in the genomic clones spanning all the four bkp's, suggesting their possible involvement in the rearrangement. No clinical phenotype was associated with this balanced rearrangement in the mother and a number of other carriers in the same family.

Abnormalities, Multiple↗
PubMed2004

Haplotype analysis of BRCA1 gene reveals a new gene rearrangement: characterization of a 19.9 KBP deletion.

Germ-line mutations in the BRCA1 gene cause hereditary predisposition to breast and ovarian cancer. BRCA1 and BRCA2 mutations account for about 40% of high-risk families. Mutation-screening methods generally focus on genomic DNA and are usually PCR based; they enable the detection of sequence alterations such as point mutations and small deletions and insertions. However, they do not allow the detection of partial or entire exon(s) loss, because the presence of the homologous allele results in a positive PCR signal, giving rise to a false-negative result. Identification of unusual haplotypes in patient samples by an expectation maximization algorithm has recently been suggested as a method for identifying hemizygous regions caused by large intragenic deletions. Using a similar approach, we identified a novel BRCA1 genomic rearrangement in a breast/ovarian cancer family negative at the first mutation screening; we detected a deletion encompassing exons 14-19, probably due to replication slippage between Alu sequences.

Alu Elements↗
PubMed1999

Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells.

Expression of the human multidrug resistance 1 gene (MDR1), which encodes the P-glycoprotein transmembrane efflux pump, has been associated with treatment failure of some leukemias, primarily acute myeloid leukemia (AML). To elucidate the epigenetic events associated with overexpression of MDR1 in AML, we analyzed the methylation status of a 2000 bp region within the MDR1 locus using a bisulphite genomic sequencing technique. A CpG-rich domain, approximately 1 kb in size, encompasses the promoter region, exon I, and intron I. This domain was found to be relatively unmethylated in five out of six primary and cultured human hematopoietic cells, as well as five out of six AML patient samples, independent of the MDR1 phenotype. The data suggest that the methylation status of the CpG-rich domain does not act as a 'switch' to regulate expression of the MDR1 gene. In addition, we found an upstream Alu repeat sequence to be unmethylated in three out of five cultured hematopoietic cell lines, both MDR1 expressing and non-expressing. However, analysis of primary CD8-positive T cells and AML patient samples revealed dense methylation of this region which is consistent with methylation of Alu repeat sequences observed in somatic tissues.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Molecular analysis of chromosomal breakpoints in three examples of chromosomal translocation involving the TEL gene.

The TEL gene is involved in several chromosomal abnormalities of human hematopoietic malignancies. The chromosome 12 breakpoints frequently lie within the fifth intron of the gene, particularly in the most frequent translocation involving TEL, the t(12;21)(p13;q22). In order to search for a peculiar mechanism involved in the genesis of these translocations, we have established the sequence of two t(12;21) and a t(9;12)(q24;p13) breakpoints. Our data do not reveal the involvement of VDJ recombinase activity or Alu sequences but favor the occurrence of staggered breaks and DNA repair activity in the genesis of these translocations.

Alleles↗
PubMed1999

Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast/ovarian cancer families.

Most of the hereditary breast cancers are attributed to constitutive alterations of either BRCA1 or BRCA2 genes; nonetheless, germline mutations of these genes in 'high risk' families are found less frequently than expected from linkage data. Recent findings suggest that major genomic rearrangements of the BRCA1 gene might account for at least some of the apparently mutation negative cases. We studied 60 affected probands belonging to families with a strong history of breast and/or ovarian cancer who scored negative for BRCA1 gene mutations by PTT and SSCP analysis. DNA was analysed by the Southern blotting procedure using three different restriction enzymes, and two probes obtained by RT-PCR of the 5' and 3' BRCA1 coding sequence. A 3 kb deletion encompassing exon 17 and causing a frameshift mutation was identified in two independently ascertained families. RT-PCR and long-range DNA PCR were employed to characterize the rearrangement that was finally shown to be the result of a recombination between two very similar Alu repeats. This type of mutation is not identified by the conventional methods of mutation detection which are based on PCR amplification of single exons. Therefore, further search for gene rearrangements is needed to better define the proportion of 'high risk' families that might be explained by gross genomic alterations of the BRCA1 gene.

Alu Elements↗
PubMed1999

A novel human DNA-binding protein with sequence similarity to a subfamily of redox proteins which is able to repress RNA-polymerase-III-driven transcription of the Alu-family retroposons in vitro.

In this study we identified a novel protein which may contribute to the transcriptional inactivity of Alu retroposons in vivo. A human cDNA clone encoding this protein (ACR1) was isolated from a human expression library using South-western screening with an Alu subfragment, implicated in the regulation of Alu in vitro transcription and interacting with a HeLa nuclear protein down-regulated in adenovirus-infected cells. Bacterially expressed ACR1 is demonstrated to inhibit RNA polymerase III (Pol III)-dependent Alu transcription in vitro but showed no repression of transcription of a tRNA gene or of a reporter gene under control of a Pol II promoter. ACR1 mRNA is also found to be down-regulated in adenovirus-infected HeLa cells, consistent with a possible repressor function of the protein in vivo. ACR1 is mainly (but not exclusively) located in cytoplasm and appears to be a member of a weakly characterized redox protein family having a central, highly conserved sequence motif, PGAFTPXCXXXXLP. One member of the family identified earlier as peroxisomal membrane protein (PMP)20 is known to interact in a sequence-specific manner with a yeast homolog of mammalian cyclosporin-A-binding protein cyclophilin, and mammalian cyclophilin A (an abundant ubiquitously expressed protein) is known to interact with human transcriptional repressor YY1, which is a major sequence-specific Alu-binding protein in human cells. It appears, therefore, that transcriptional silencing of Alu in vivo is a result of complex interactions of many proteins which bind to its Pol III promoter.

Adenoviridae↗
PubMed1999

New world, but not Old World, monkeys carry several genes encoding beta-microseminoprotein.

It was shown by Southern hybridization that cotton-top tamarin and common marmoset, New World monkeys, carry three or more genes encoding beta-microseminoprotein, also known as PSP94. In contrast, the genomes of Old World monkeys, as represented by rhesus macaque and sacred baboon, contain a single gene. Clones containing three different genes encoding beta-microseminoprotein were isolated from a cotton-top tamarin genomic library. They carry two complete genes of four exons and a third gene lacking the first exon. The structure suggests that the three genes are functionally active and give rise to transcripts that are approximately 86% similar in sequence. By sequencing one gene in full, it was shown that the introns carry an excess of interspersed repeats, on average 29% of the introns consist of Alu repeats. A phylogenetic analysis demonstrated that the genes probably arose in New World monkeys after the separation from Old World primates.

Alu Elements↗
PubMed2000

Alu-DNA repeat-binding protein p68 is a part of Alu-RNA containing alpha-RNP.

An Alu-DNA repeat-binding protein with a molecular mass of 68 kDa (p68) is identified in the somatic human cell nucleoplasm. Gel mobility shift assay (GMSA), South-western blotting and affinity purification on DNA attached to the carrier were used in the identification. GMSA revealed multiple complexes with the exponential dependence of their relative mobility. A narrow binding site of the p68 was revealed using synthetic oligonucleotides. It is located between the A-box and B-box of the RNA polymerase III promoter and is identical to that reported for the Alu-binding protein from human spermatozoids. The same narrow binding site, the similarity of the isolation procedure from germ and somatic cells, and similar binding properties and molecular masses suggest homology of the two proteins. Antibodies raised against Alu-protein complexes led to hypershift of the complexes in GMSA and stained p68 in active fractions in human spermatozoids and in Alu-RNA-containing alpha-RNP particles. Immunofluorescence of a HeLa cell monolayer revealed an intranuclear dot pattern with the dots corresponding to euchromatin areas and some dots located at the cell periphery in the cytoplasm. alpha-RNP particles bound Alu-DNA in vitro and contained p68 as shown using the immunogold procedure. Alu-DNA binding activity was revealed in cytoplasm as well as in nucleoplasm. The possible nature of the main Alu-DNA binding protein and its involvement in the particle structure are discussed.

Alu Elements↗
PubMed2004

Alu insertion polymorphisms in the Balkans and the origins of the Aromuns.

We have analysed 11 human-specific Alu insertion polymorphisms in the Balkans to elucidate the origins of the Aromuns, a linguistic isolate inhabiting scattered areas in the Balkan Peninsula. Four Aromun samples (two from the Republic of Macedonia, one from Albania, and one from Romania) and five neighbouring populations (Macedonians, Albanians, Romanians, Greeks, and Turks) were analysed by means of genetic distances, principal components and analyses of the molecular variance (AMOVA). Three hypotheses were tested: Aromuns are Romanophonic Greeks; the result of a Romanian southward migration; or local descendants of the Thracians. The analyses show that the Aromuns do not constitute a homogeneous group separated from the rest of the Balkan populations. Grouping by language or geography does not explain the genetic differences observed in the region, suggesting a lack of genetic structure in the area. Aromuns do not seem to be particularly related to Greeks, Romanians, or to other Romance speakers. The Aromuns might have their origin to the south of the Danube river, with extensive gene flow with the neighbouring populations. The present results suggest a common ancestry of all Balkan populations, including Aromuns, with a lack of correlation between genetic differentiation and language or ethnicity, stressing that no major migration barriers have existed in the making of the complex Balkan human puzzle.

Alu Elements↗
PubMed2004

A tale of aborigines, conquerors and slaves: Alu insertion polymorphisms and the peopling of Canary Islands.

Classical, mitochondrial DNA (mtDNA) and Y chromosome markers have been used to examine the genetic admixture in present day inhabitants of the Canary Islands. In this study, we report the analysis of ten autosomal Alu insertion polymorphisms in 364 samples from the seven main islands of the Archipelago, and their comparison to continental samples. The detection of population-specific alleles from the Iberian Peninsula and Northwest Africa, as well as their affinities on the basis of genetic distances and principal component analysis, support a clear link between these populations. Coincident with previous results, the Canarian gene pool can be distinguished as being halfway between those of its putative parents, although with a major Iberian contribution (62-78%). Both the substantial Northwest African contribution (23-38%), and the minor sub-Saharan African input (3%), suggest that the genetic legacy from the aborigines and slaves still persists in the Canary Islanders.

Adolescent↗
PubMed2005

Worldwide genetic variation at the 3'-UTR region of the LDLR gene: possible influence of natural selection.

The low density lipoprotein receptor gene (LDLR) contains many Alu insertions, and is especially Alu-rich at its 3'-untranslated region (3'-UTR). Previous studies suggested that the LDLR 3'-UTR could regulate gene expression by the stabilization of its mRNA. Given the faster Alu evolutionary rate, and wondering about its consequences in a possibly regulatory locus, we have studied approximately 800 bp of 222 chromosomes from individuals of African, Asian, Caucasian and Amerind ancestry, to better understand the evolution of the worldwide genetic diversity at this locus. Twenty-one polymorphic sites, distributed in 15 haplotypes, were found. High genetic diversity was observed, concentrated in one Alu insertion (Alu U), which also shows a fast evolutionary rate. Genetic diversity is similar in all populations except Amerinds, suggesting a bottleneck during the peopling of the American continent. Three haplotype clusters (A, B, C) are distinguished, cluster A being the most recently formed (approximately 500,000 years ago). No clear geographic structure emerges from the haplotype network, the global F(st) (0.079) being lower than the average for the human genome. When ancestral population growth is taken into account, neutrality statistics are higher than expected, possibly suggesting the action of balancing selection worldwide.

3' Untranslated Regions↗