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PubMed1988

Structure of the human blood platelet membrane glycoprotein Ib alpha gene.

The gene for human platelet glycoprotein Ib alpha-chain has been cloned from a genomic cosmid library using a partial cDNA clone as probe. 3530 bp were sequenced including the entire transcribed part, as well as additional 5' and 3' regions. A single intron was found 6 bp upstream of the ATG initiation codon. An exceptionally long exon was identical to the recently published cDNA sequence (1). The 5' upstream promoter region is atypical for eukaryotic genes with only a weak homology to the characteristic promoter consensus sequences. The 3' region contains two repetitive Alu elements, belonging to distinct subfamilies, connected by an oligo(dA) linker.

Amino Acid Sequence↗

PubMed1997

Alternative splicing in lecithin:cholesterol acyltransferase mRNA: an evolutionary paradigm in humans and great apes.

Lecithin:cholesterol acyltransferase (LCAT), an important enzyme affecting reverse cholesterol transport, is expressed in liver and cultured fibroblasts. Sequencing of LCAT cDNA clones demonstrated the coexistence of two mRNA products. In addition to the normal transcript, we identified an alternate message with a splice-mediated insertion of a 95 bp Alu cassette at the junction of exons 5 and 6. In humans, the alternate transcript represents 5-20% of the complete LCAT message in cultured fibroblasts and liver. It is present in humans and the great apes but not in lesser apes (gibbon, siamang) or lower-order primates (e.g., old or new world monkeys). Sequencing of intron 5 of the LCAT locus in several primates revealed a G-->A transition at the splice donor recognition site in the Alu repeat of the gibbon and a G-->A substitution in the last position of the 95 bp Alu sequence of the rhesus monkey, an old world monkey. Both substitutions have been associated with exon skipping in other genes. These results demonstrate that alternative splicing of LCAT mRNA is variant among primates and suggest a potential role of Alu elements in the evolutionary diversity of proteins.

Alternative Splicing↗

PubMed1997

Molecular evolution of the second ancient human mariner transposon, Hsmar2, illustrates patterns of neutral evolution in the human genome lineage.

A consensus sequence for the second ancient mariner identified in the human genome, Hsmar2, was constructed by majority rule from full-length and partial sequences of 44 of the +/-1000 copies in the genome. This 1300 base pair (bp) consensus has 31 bp imperfect terminal repeats (ITRs) and encodes a 351 amino acid (aa) mariner transposase. The sequence of this transposase has allowed classification of Hsmar2 as a basal lineage of the irritans subfamily of mariners, sharing at most 38% aa identity with other members of the subfamily. The individual copies in the human genome are all highly mutated from the consensus, having suffered numerous small and some large insertions and deletions (indels), including many insertions of S and J subfamily Alu elements. The copies differ, on average, from the consensus by 11.6%, have suffered 11.8 indels per kilobase (kb), and only 3.7% of the 30 hypermutable CpG dinucleotide pairs in the consensus remain intact. This level of divergence indicates that the ancestrally active Hsmar2 element represented by the consensus was present in the human genome lineage about 80 million years (Myr) ago. Each copy has apparently evolved since then largely independently of the others, and with little constraint on its transposase coding capacity. This pattern of molecular evolution fits the current model for mariner transposon evolution. These copies provide multiple independent datasets for evaluating the pattern of neutral evolution in the human genome, for example, they confirm that most indels are very short and that deletions are twice as common as insertions.

Amino Acid Sequence↗

PubMed1998

Angiotensin-converting enzyme genotypes and risk for myocardial infarction in women.

OBJECTIVES: We tested for an association between the angiotensin-converting enzyme (ACE) DD polymorphic genotype and myocardial infarction (MI) in a sample group composed exclusively of women. BACKGROUND: The human ACE gene occurs with either an insertion (I allele) or a deletion (D allele) of a 287-base pair (bp) Alu element. Part of the variance in serum ACE levels may be accounted for by this polymorphism. Also, the DD genotype has been associated with an increased risk of MI in predominantly male populations. However, the risk in women is poorly defined. METHODS: Genomic DNA was extracted from buffy coat blood using a phenol/chloroform method. Angiotensin-converting enzyme alleles were identified using primers to bracket the insertion region in intron 16. Amplification using polymerase chain reaction allowed identification of a 490-bp (I allele) or a 190-bp (D allele) product, or both. RESULTS: Allelic and genotypic frequencies in control subjects were similar to those reported in mostly male populations, and frequencies of genotypes were in the Hardy-Weinberg equilibrium. In contrast, the distribution of genotypes in patients with MI diverged from the equilibrium. Specifically, DD genotypic frequency was increased in women with (n = 141) versus without (n = 338) a previous MI (39% vs. 29%, odds ratio [OR] 1.54, 95% confidence interval 1.02 to 2.32, p < 0.04). Risk was particularly increased in women <60 years old (OR 2.04, p < 0.05). In contrast, the DD genotype did not predict angiographic coronary artery disease. CONCLUSIONS: Consistent with findings in male-dominated populations, a modest association of the ACE DD genotype with MI was found in women. The basis for this association requires further study.

Aged↗

PubMed2003

Linkage disequilibrium analysis of the human adenosine deaminase (ada) gene provides evidence for a lack of correlation between hot spots of equal and unequal homologous recombination.

The linkage disequilibrium (LD) pattern within the adenosine deaminase (ADA) gene was analyzed by studying 13 polymorphic loci in 137 families from two European and three African populations. Evidence for the presence of a 12-kb meiotic crossover hot spot, spanning part of the first and the second intron and flanked by regions of reduced recombination activity, was obtained. Moreover, segregation analysis of 113 informative meioses revealed two recombination events that are internal or overlap the 12-kb region, thus suggesting a recombination rate for the hot-spot region about 50-fold higher than the mean rate across the human genome. Within the hot spot, a 144-bp palindromic sequence was also identified and its possible involvement in the recombination process is discussed. The 12-kb region characterized by the low degree of LD does not include the 3.2-kb region that is deleted, as a result of recurrent unequal homologous recombination between two Alu elements, in patients affected by autosomal severe combined immunodeficiency. This observation provides the first evidence for an absence of correlation between hot spots of equal and unequal homologous recombination.

Adenosine Deaminase↗

PubMed1990

Population structure of the human pseudoautosomal boundary.

The mammalian sex chromosomes are composed of two genetically distinct segments: the pseudoautosomal region, where recombination occurs between the X and Y chromosomes, and the sex chromosome-specific parts. Between these two segments the human sex chromosomes differ by the insertion of an Alu element on the Y chromosome. We have surveyed the sequence variation in the boundary region using the polymerase chain reaction. Fifty seven Y and sixty X chromosomes from ten different human populations were analysed. The X chromosomes were found to be polymorphic at five positions in a 300-base-pair region. By contrast, all Y chromosomes were identical except for one distal polymorphism shared with the X chromosome.

Base Sequence↗

PubMed2002

A chromatin remodelling complex that loads cohesin onto human chromosomes.

Nucleosomal DNA is arranged in a higher-order structure that presents a barrier to most cellular processes involving protein DNA interactions. The cellular machinery involved in sister chromatid cohesion, the cohesin complex, also requires access to the nucleosomal DNA to perform its function in chromosome segregation. The machineries that provide this accessibility are termed chromatin remodelling factors. Here, we report the isolation of a human ISWI (SNF2h)-containing chromatin remodelling complex that encompasses components of the cohesin and NuRD complexes. We show that the hRAD21 subunit of the cohesin complex directly interacts with the ATPase subunit SNF2h. Mapping of hRAD21, SNF2h and Mi2 binding sites by chromatin immunoprecipitation experiments reveals the specific association of these three proteins with human DNA elements containing Alu sequences. We find a correlation between modification of histone tails and association of the SNF2h/cohesin complex with chromatin. Moreover, we show that the association of the cohesin complex with chromatin can be regulated by the state of DNA methylation. Finally, we present evidence pointing to a role for the ATPase activity of SNF2h in the loading of hRAD21 on chromatin.

Adenosine Triphosphatases↗

PubMed2005

Angiotensin-converting enzyme gene polymorphisms and obesity: an examination of three black populations.

We examined the association between obesity and 13 angiotensin-converting enzyme (ACE) gene polymorphisms, including the presence (I) or absence (D) of an Alu element in intron 16 (I/D polymorphism), and performed haplotype analysis using data collected from participants of a community survey of hypertension among blacks living in Ibadan, Nigeria; Spanish Town, Jamaica; and Chicago, IL. Transmission distortion of ACE gene polymorphisms and haplotypes from heterozygous parents to affected offspring was examined in each study population. To estimate haplotypes, polymorphisms were divided into three groups based on their position on the ACE gene. No ACE gene polymorphism was consistently overtransmitted from parents to obese offspring among the three populations. However, the haplotype ACE1-ACE5 TACAT, located in the promoter region, was significantly overtransmitted from parents to obese offspring in both the U.S. and Nigerian populations. No haplotype was significantly overtransmitted from parents to obese offspring among the Jamaicans. In conclusion, we noted the overtransmission of a particular ACE gene promoter region haplotype from parents to obese offspring in two separate black populations. These data suggest that ACE gene polymorphisms may influence the development of weight gain.

Adult↗

PubMed2026

Two cases of mosaic germline SVA insertions in SMARCB1: implications for rhabdoid tumour predisposition diagnosis.

Rhabdoid tumour predisposition syndrome (RTPS) is a highly penetrant cancer predisposition syndrome caused by germline variants in SMARCB1 or less frequently in SMARCA4. Genetic testing for this syndrome involves sequence and deletion/duplication analysis of these two genes. Standard clinical testing is limited in detecting structural variants. Here we describe two patients who tested negative on standard clinical germline panel testing for RTPS but were each found to have a mosaic germline insertion of an SVA (SINE-VNTR-Alu) element in the SMARCB1 gene by more advanced comprehensive genomic analysis. These two cases demonstrate the importance of structural variants and broader genomic sequencing for individuals suspected of having an underlying germline cancer predisposition syndrome, such as RTPS.

Journal Article↗

PubMed2001

Transcriptional and translational mechanisms of cytochrome b5 reductase isoenzyme generation in humans.

Cytochrome b5 reductase (b5R) is an essential enzyme that exists in soluble and membrane-bound isoforms, each with specific functions. In the rat, the two forms are generated from alternative transcripts differing in the first exons. In contrast, the biogenesis of b5R isoforms in the human is not yet well understood. In the present study we have detected three novel alternative exons, designated 1S, S' and 1B, located between the first alternative exon 1M and the common second exon in the human b5R gene. Accordingly, multiple M-type, S-type and SS'-type and B-type transcripts are generated. All types of human b5R transcript are expressed ubiquitously. An analysis of in vitro translation products demonstrated an alternative use of different AUG initiators resulting in the production of various human b5R protein isoforms. Our results indicate that the organization of the 5' region of the b5R gene is not conserved between rodents and humans. Insertion of Alu elements into the human b5R gene, in particular just upstream of the S/S' region, could be responsible for dynamic events of gene rearrangement during evolution.

Alternative Splicing↗

PubMed2000

Cloning and analysis of the gene encoding the human neonatal Fc receptor.

The neonatal Fc receptor, FcRn, is expressed in human placental syncytiotrophoblast, capillary endothelium, intestinal epithelium, and other tissues. By analogy with its role in the mouse, human FcRn is expected to transport maternal IgG to the foetus, and protect circulating IgG from catabolism. The larger subunit of FcRn is homologous to the alpha chains of the major histocompatibility complex (MHC) class I proteins, but is encoded outside the MHC on chromosome 19. We report the isolation of clones encoding the alpha chain of human FcRn from chromosome 19-specific libraries. The sequence revealed a similar organization to classical and non-classical MHC, and MHC-related genes. Compared with classical MHC class I genes, the human FcRn alpha chain gene has expanded by acquiring many repetitive sequences in its introns, including multiple Alu elements in the fourth intron. Primer extension analysis showed that there are two transcription initiation sites in the upstream flanking sequence.

Amino Acid Sequence↗

PubMed1997

Diversity of the human Y chromosome of South American Amerindians: a comparison with blacks, whites, and Japanese from Brazil.

We defined the Y-chromosome haplotypes on the basis of six polymorphic sites: an Alu-element insertion (YAP), a single-base change (C-->T at DYS199), one trinucleotide repeat (DYS392) and three tetranucleotide repeats (DYS393, DYS390 and DYS19). Among 140 Y chromosomes from Whites, Blacks, Japanese and Amerindians we identified 67 different haplotypes, the majority of them population-specific; only seven haplotypes were shared by three different racial groups, mostly owing to admixture. Overall, three main lineages can be defined on the basis of the YAP/DYS199/DYS392 markers: (a) a predominant /-/C/10/13/22 (or) 23/ lineage, observed among all racial groups; (b) a/+/C/ lineage which predominates among Blacks (comprising mainly the sublineage /+/C/10/13/), although it is eventually found among Japanese and Whites; and (c) a /-/T/ lineage observed only among Amerindians (comprising mainly the sublineage /-/T/13/13/). The decreasing haplotype diversity of the three lineages agrees with the idea that the first is the most ancient, while the last is the more recent. The data also indicate that the YAP insertion occurred in a /-/C/10/13/ chromosome and the C-->T mutation occurred in a /-/C/13/13/ chromosome. Finally, the data suggest that at least two Y-chromosome lineages (/-/C/13/ and /-/T/13/) contributed to the early peopling of the Americas, and supports the hypothesis that /-/T/13/ could be derived from /-/C/13/ and that both haplotypes could be present in the ancestral populations that peopled the continent.

Alleles↗

PubMed1996

Complete structure of the human alpha-albumin gene, a new member of the serum albumin multigene family.

The nucleotide sequence of the human alpha-albumin gene, including 887 bp of the 5'-flanking region and 1311 bp of the 3-flanking region (24,454 in total), was determined from three overlapping lambda phage clones. The sequence spans 22,256 bp from the cap site to the polyadenylylation site, revealing a gene structure of 15 exons separated by 14 introns. The methionine initiation codon ATG is within exon 1; the termination codon TGA is within exon 14. Exon 15 is entirely untranslated and contains the polyadenylylation signal AATAAA. The deduced polypeptide chain is composed of a 21-amino-acid leader peptide, followed by 578 amino acids of the mature protein. There are seven repetitive DNA elements (Alu and Kpn) in the introns and 3-flanking region. The sizes of the 15 alpha-albumin exons match closely those of the albumin, alpha-fetoprotein, and vitamin D-binding protein genes. The exons are symmetrically placed within the three domains of the individual proteins, and they share a characteristic codon splitting pattern that is conserved among members of the gene family. The results provide strong evidence that alpha-albumin belongs to, and most likely completes with, the serum albumin gene family. Based on structural similarity, alpha-albumin appears to be most closely related to alpha-fetoprotein. The complete structure of this family of four tandemly linked genes provides a well-characterized approximately 200 kb locus in the 4q subcentromeric region of the human genome.

Albumins↗

PubMed1996

The KRAB zinc finger gene ZNF74 encodes an RNA-binding protein tightly associated with the nuclear matrix.

We previously cloned ZNF74, a developmentally expressed zinc finger gene commonly deleted in DiGeorge syndrome. Here, the intron/exon organization of the human gene and the functional properties of the expressed protein are presented. This zinc finger gene from the transcription factor IIIA/Kruppel family contains three exons. A truncated Kruppel-associated box (KRAB) located at the N terminus of the predicted 64-kDa zinc finger protein is encoded by exon 2. The remainder of the protein including the zinc finger domain as well as the 3'-untranslated region (UTR) is encoded by exon 3. Both 5'-UTR (exon 1) and 3'-UTR contain repetitive Alu elements. In vitro translation of a cDNA encoding the entire ZNF74 coding region produced a 63-kDa protein as determined on sodium dodecyl sulfate-polyacrylamide gel. A bacterially expressed fusion protein shown to bind tightly to 65zinc was used to test the nucleic acid binding properties of ZNF74. By RNA binding assays, ZNF74 was found to bind specifically to poly(U) and poly(G) RNA homopolymers. The restricted binding to these homopolymers and not to poly(A) and poly(C) suggested that ZNF74 displays RNA sequence preferences. RNA binding was mediated by the zinc finger domain. Immunofluorescence studies on transfected cells revealed ZNF74 nuclear localization. The labeling pattern observed in the nuclei clearly excluded the nucleoli. The zinc finger region lacks a classical nuclear localization signal but was found to be responsible for nuclear targeting. Subcellular and in situ sequential fractionations further showed that ZNF74 is associated with the nuclear matrix. The RNA binding properties of this protein and its tight association with the nuclear matrix, a subnuclear compartment involved in DNA replication as well as RNA synthesis and processing, suggest a role for ZNF74 in RNA metabolism.

Amino Acid Sequence↗

PubMed2002

Structural determinants of BRCA1 translational regulation.

The BRCA1 gene is involved in sporadic breast and ovarian cancer mainly through reduced expression. BRCA1 mRNAs containing different leader sequences show different patterns of expression. In a normal mammary gland mRNA with a shorter leader sequence, 5'-UTRa is expressed only, whereas in breast cancer tissue mRNA with a longer leader, 5'-UTRb is expressed also. We show that the translation efficiency of transcripts containing 5'-UTRb is 10 times lower than those containing 5'-UTRa. The structures of 5'-UTRa and 5'-UTRb were determined by chemical and enzymatic probing aided by a new method developed for monitoring the number of co-existing stable conformers. Specific factors responsible for reduced translation of mRNA containing 5'-UTRb were determined using a variety of transcripts with mutations in the leader sequence. These factors include a stable secondary structure formed by truncated Alu element and upstream AUG codons. The novel mechanism by which BRCA1 may be involved in sporadic breast and ovarian cancer is proposed. It is based on the expression patterns of BRCA1 mRNAs and differences in their translatability. According to this mechanism the deregulation of the BRCA1 transcription in cancer, resulting in a higher proportion of translationally inhibited transcripts containing 5'-UTRb, contributes to the decrease in the BRCA1 protein observed in sporadic breast and ovarian cancers.

3' Untranslated Regions↗

PubMed2005

Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS.

To identify genetic factors contributing to psoriasis susceptibility, gene expression profiles of uninvolved epidermis from psoriatic patients and epidermis from healthy individuals were compared. Besides already characterized genes, we identified a cDNA with yet unknown functions, which we further characterized and named PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). In silico structural and homology studies suggested that PRINS may function as a noncoding RNA. PRINS harbors two Alu elements, it is transcribed by RNA polymerase II, and it is expressed at different levels in various human tissues. Real time reverse transcription-PCR analysis showed that PRINS was expressed higher in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesional and healthy epidermis, suggesting a role for PRINS in psoriasis susceptibility. PRINS is regulated by the proliferation and differentiation state of keratinocytes. Treatment with T-lymphokines, known to precipitate psoriatic symptoms, decreased PRINS expression in the uninvolved psoriatic but not in healthy epidermis. Real time reverse transcription-PCR analysis showed that stress signals such as ultraviolet-B irradiation, viral infection (herpes simplex virus), and translational inhibition increased the RNA level of PRINS. Gene-specific silencing of PRINS by RNA interference revealed that down-regulation of PRINS impairs cell viability after serum starvation but not under normal serum conditions. Our findings suggest that PRINS functions as a noncoding regulatory RNA, playing a protective role in cells exposed to stress. Furthermore, elevated PRINS expression in the epidermis may contribute to psoriasis susceptibility.

Base Sequence↗

PubMed1991

The genomic structure of human V beta 6 T cell antigen receptor genes.

Six genomic clones were characterized containing members of the human V beta 6 subfamily of T cell antigen receptor genes. There were four major findings. (a) New V beta genes were discovered, including V beta 6.10, V beta 13.4, V beta 13.5, and V beta 5.5. (b) Members of the V beta 13, V beta 6, and V beta 5 subfamilies cluster together in the V beta locus and may have evolved through multiple duplication events of an ancestral cassette containing V beta 13-V beta 6-V beta 5 genes. These V beta subfamilies are used by an estimated one-third of T cells in humans and probably represent a highly useful component of the V beta repertoire. (c) The promoters of V beta 13, V beta 6, and V beta 5 genes contain conserved decamer motifs, but discrete differences were observed between promoters of different V beta subfamilies, raising the question of different transcriptional control depending on V beta subfamily usage. (d) The new V beta 6.10 gene is probably a pseudogene, which may have been inactivated due to retrotransposition of Alu elements into its promoter region, a mutation affecting a highly conserved cysteine residue or mutations of the 3' recombinase signal sequence.

Amino Acid Sequence↗

PubMed1994

Human natural resistance-associated macrophage protein: cDNA cloning, chromosomal mapping, genomic organization, and tissue-specific expression.

Natural resistance to infection with unrelated intracellular parasites such as Mycobacteria, Salmonella, and Leishmania is controlled in the mouse by a single gene on chromosome 1, designated Bcg, Ity, or Lsh. A candidate gene for Bcg, designated natural resistance-associated macrophage protein (Nramp), has been isolated and shown to encode a novel macrophage-specific membrane protein, which is altered in susceptible animals. We have cloned and characterized cDNA clones corresponding to the human NRAMP gene. Nucleotide and predicted amino acid sequence analyses indicate that the human NRAMP polypeptide encodes a 550-amino acid residue membrane protein with 10-12 putative transmembrane domains, two N-linked glycosylation sites, and an evolutionary conserved consensus transport motif. Identification of genomic clones corresponding to human NRAMP indicates that the gene maps to chromosome 2q35 within a group of syntenic loci conserved with proximal mouse 1. The gene is composed of at least 15 exons, with several exons encoding discrete predicted structural domains of the protein. These studies have also identified an alternatively spliced exon encoded by an Alu element present within intron 4. Although this novel exon was found expressed in vivo, it would introduce a termination codon in the downstream exon V, resulting in a severely truncated protein. Northern blot analyses indicate that NRAMP mRNA expression is tightly controlled in a tissue-specific fashion, with the highest sites of expression being peripheral blood leukocytes, lungs, and spleen. Additional RNA expression studies in cultured cells identified the macrophage as a site of expression of human NRAMP and indicated that increased expression was correlated with an advanced state of differentiation of this lineage.

Alternative Splicing↗