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PubMed1989

[DNA fingerprints and hypervariable regions: genetic marker with many application potentials in medicine and biology].

DNA polymorphisms are based on variations in the nucleotide sequences of the DNA within a given population and are transmitted from parents to offspring by Mendelian inheritance. Most of these mutations are phenotypically silent. Two different types of DNA polymorphisms are restriction fragment length polymorphisms and highly variable regions (HVRs), the latter with many different alleles at a given locus. Molecular probes for HVRs (or DNA minisatellites) can detect a great number of cross-hybridising fragments dispersed throughout the genome. The polymorphic patterns of these fragments are completely individual-specific, hence termed DNA "fingerprints". DNA "fingerprinting" has been shown to be a powerful tool for establishing family relationships, for example in paternity disputes, and for the positive identification of individuals in forensic medicine. The technique may be used to document marrow engraftment in patients who have undergone allogeneic bone marrow transplantation. DNA "fingerprinting" is a new method of assessing clonality in human tumours by identifying clonal somatic mutations in the tumour DNA. Cloning of individual DNA "fingerprint" fragments yields locus-specific HVR probes which, due to their high rate of heterozygosity, are ideal for linkage analysis and prenatal diagnosis in single gene disorders. This is exemplified by adult polycystic kidney disease, which has been found by a 3'alpha-globin-HVR probe to be closely linked to the alpha-globin-gene cluster on chromosome 16p. Locus-specific HVR probes have been used for the molecular diagnosis of clonal chromosomal deletions or loss of heterozygosity at particular loci in a large variety of tumours. These findings are the basis for the identification of anti-oncogenes or putative tumour-suppressor genes in the human genome.

Animals↗
PubMed2004

Contrasting modes of natural selection acting on pigmentation genes in the Drosophila dunni subgroup.

Genes that encode for divergent adaptive traits may have genealogies that contrast with those from loci that are not functionally involved in differentiation. Here, we examine DNA sequence variation among the species of the eastern Caribbean Drosophila dunni subgroup at two loci, yellow and dopa decaboxylase (Ddc), which both play integral roles in pigmentation patterning of adult Drosophila. Phylogenetic analyses of these loci produce gene genealogies with topologies that mirror those described for other nuclear genes: the six morphologically distinct species within the subgroup are divided into only three lineages, with one lineage containing four species that share extensive ancestral polymorphism. At the Ddc locus these major lineages are delineated only by silent site variation. We observe a significantly higher rate of synonymous site divergence than non-synonymous divergence, consistent with strong purifying selection acting on the locus. In contrast, the yellow locus exhibits patterns of amino acid divergence and nucleotide diversity that are consistent with recent diversifying selection acting in two different lineages. This selection appears to be targeting amino acid variants in the signal sequence of the Yellow protein, a region which is tightly constrained among members of the larger D. cardini radiation. This result highlights not only the potential importance of yellow in the evolution of divergent pigmentation patterns among members of the D. dunni subgroup, but also hints that variation in signal peptide sequences may play a role in phenotypic diversification.

Amino Acid Sequence↗
PubMed1989

HLA-DR and -DQ epitopes and monoclonal antibody specificity.

The polymorphism of the HLA system-originally studied serologically using antisera from multiparous women and cellularly using the mixed lymphocyte reaction-has now been further revealed by the use of monoclonal antibodies and, at the most basic level, by the nucleotide and amino acid sequences of the different alleles. In this article, Steven Marsh and Julia Bodmer examine the specificity of mainly well-known HLA-DR and HLA-DQ monoclonal antibodies and postulate the positions of their binding sites, or at least of the polymorphic sites determining their patterns of reactivity. The publication together of all available amino acid sequences of the first domain of the DR beta and DQ alpha and the DQ beta chains (updated and corrected where necessary in collaboration with their authors) provides a useful tool with which to identify binding sites of other antibodies and perhaps to attempt to correlate their position in the structure with their function. Outlines of strategies to produce a wider range of polymorphic antibodies are discussed.

Amino Acid Sequence↗
PubMed2005

Haplotype-based genetics in mice and rats.

Haplotype blocks are conceptually defined as genomic segments harbouring sets of coupled polymorphisms that reflect a common ancestral origin. Experimentally, however, haplotype blocks are characterized using computational algorithms based on incomplete inventories of polymorphisms. Haplotype blocks and their deduced strain-distribution patterns are considered to be extremely powerful for use in genetic association and mapping experiments in laboratory mice and rats. However, recent high-density SNP screening in commonly used mouse inbred strains reveals a complex pattern, suggesting that the current expectations for the use of haplotype blocks in genetic mapping will have to be revisited.

Algorithms↗
PubMed2005

A G-to-A transition at the fifth position of intron-32 of the dystrophin gene inactivates a splice-donor site both in vivo and in vitro.

The splicing pattern of pre-mRNA is unpredictable in genes harboring a single-nucleotide change within the consensus sequence of a splice-donor site. In the dystrophin gene, a transition from G to A at the fifth position of intron-32 (4518+5G > A) has been reported as a polymorphism within the consensus sequence or a mutation identified in Duchenne muscular dystrophy (DMD). Here, we report both in vivo and in vitro evidence that shows inactivation of the splice-donor site caused by this mutation. In one Japanese DMD case, two novel dystrophin mRNAs were identified in the patient's lymphocytes, one with a 98 bp deletion of the 3' end of exon-32 (dys32-98) and the other with a 28 bp intron retained between exons 32 and 33 (dys32 + 28). Genomic sequencing disclosed a single-nucleotide change from G to A at the fifth position of intron-32 (4518+5G > A). To demonstrate in vitro the inactivation of this splice-donor site by this nucleotide change, mini-dystrophin genes comprising three exons harboring either normal or mutant intron-32 sequences were expressed in HeLa cells, and the splicing products were analyzed by reverse-transcription PCR amplification. A normal transcript consisting of three exons was obtained from the normal construct. From the mutant, we obtained one product containing a 98 bp deletion at the 3' end of exon-32, indicating complete inactivation of the native splice-donor site. Thus, both in vivo and in vitro experiments demonstrate that 4518+5G > A causes a splicing error leading to transcript termination; it did not behave like a silent polymorphism. Our results indicate that the in vitro splicing system is a powerful tool for determining the underlying mechanism of a disease-causing mutation in a splicing consensus sequence.

Base Sequence↗
PubMed1997

Diversity and age of the four major mtDNA haplogroups, and their implications for the peopling of the New World.

Despite considerable investigation, two main questions on the origin of Native Americans remain the topic of intense debate-namely, the number and time of the migration(s) into the Americas. Using the 720 available Amerindian mtDNA control-region sequences, we reanalyzed the nucleotide diversity found within each of the four major mtDNA haplogroups (A-D) thought to have been present in the colonization of the New World. We first verified whether the within-haplogroup sequence diversity could be used as a measure of the haplogroup's age. The pattern of shared polymorphism, the mismatch distribution, the phylogenetic trees, the value of Tajima's D, and the computer simulations all suggested that the four haplogroups underwent a bottleneck followed by a large population expansion. The four haplogroup diversities were very similar to each other, offering a strong support for their single origin. They suggested that the beginning of the Native Americans' ancestral-population differentiation occurred approximately 30,000-40,000 years before the present (ybp), with a 95%-confidence-interval lower bound of approximately 25,000 ybp. These values are in good agreement with the New World-settlement model that we have presented elsewhere, extending the results initially found for haplogroup A to the three other major groups of mtDNA sequences found in the Americas. These results put the peopling of the Americas clearly in an early, pre-Clovis time frame.

Americas↗
PubMed2000

Phylogenetic network of the mtDNA haplogroup U in Northern Finland based on sequence analysis of the complete coding region by conformation-sensitive gel electrophoresis.

Mutations in mtDNA have accumulated sequentially, and maternal lineages have diverged to form population-specific genotypes. Classification of the genotypes has been made based on differences found in restriction fragment analysis of the coding region or in the sequence of the hypervariable segment I. Both methods have shortcomings, as the former may not detect all the important polymorphisms and the latter makes use of a segment containing hypervariable nucleotide positions. Here, we have used conformation-sensitive gel electrophoresis (CSGE) to detect polymorphisms within the coding region of mtDNA from 22 Finns belonging to haplogroup U. Sixty-three overlapping PCR fragments covering the entire coding region were analyzed by CSGE, and the fragments that differed in their migration pattern were sequenced. CSGE proved to be a sensitive and specific method for identifying mtDNA substitutions. The phylogenetic network of the 22 coding-region sequences constituted a perfect tree, free of homoplasy, and provided several previously unidentified common polymorphisms characterizing subgroups of U. After contrasting this data with that of hypervariable segment I, we concluded that position 16192 seems to be prone to recurrent mutations and that position 16270 has experienced a back mutation. Interestingly, all 22 samples were found to belong to subcluster U5, suggesting that this subcluster is more frequent in Finns than in other European populations. Complete sequence data of the mtDNA yield a more reliable phylogenetic network and a more accurate classification of the haplogroups than previous ones. In medical genetics, such networks may help to decide between a rare polymorphism and a pathogenic mutation; in population genetics, the networks may enable more detailed analyses of population history and mtDNA evolution.

Codon↗
PubMed2002

Expression of myostatin is not altered in lines of poultry exhibiting myofiber hyper- and hypoplasia.

Decades of selective breeding have yielded lines of poultry with substantial myofiber hyperplasia, vet little is known about what genes have been altered during the course of selection. Myostatin is a strong negative regulator of muscle mass in mice and cattle and could have been one of many genetic factors contributing to increased myofiber deposition in growth-selected lines of poultry. To test this hypothesis, the sequence and expression patterns of myostatin were analyzed in growth-selected lines of chickens and quail. The sequence of broiler myostatin cDNA, amplified via reverse transcription (RT)-PCR from embryonic muscle RNA, contained no missense mutations in the coding sequence when compared to that of White Leghorn layers, although two silent single nucleotide polymorphisms (SNP) were found. Northern analysis of myostatin transcripts from embryonic pectoralis and quadriceps showed no significant differences in expression levels between broiler and layer muscle RNA. However, levels of myostatin transcripts were greatly reduced in muscles of posthatch chicks compared to embryonic muscle. Myostatin protein was also present in broiler and layer embryonic muscle at similar levels. No significant polymorphisms or differences in RNA expression levels were found in embryonic muscles of divergently selected lines of Japanese quail. These results indicate that intense artificial selection in these growth-selected lines of poultry has neither silenced the expression of myostatin nor created null alleles via mutation in the lines analyzed.

Animal Husbandry↗
PubMed2002

MHC susceptibility genes to IgA deficiency are located in different regions on different HLA haplotypes.

Familial predisposition to IgA deficiency (IgAD) suggests that genetic factors influence susceptibility. Most studies support a polygenic inheritance with a susceptibility locus (designated IGAD1) in the MHC, but its exact location is still controversial. This study aimed to map the predisposing IGAD1 locus (or loci) within the MHC by investigating the pattern of association of the disease with several markers in the region. DNA-based techniques were used to type individual alleles of four polymorphic HLA genes (HLA-DR, -DQA1, -DQB1, and HLA-B), six microsatellites (all located between HLA-DR and HLA-B), and three single nucleotide polymorphisms on the TNF gene. The frequencies of these alleles were compared among ethnically matched populations comprising 182 patients and 343 controls. Additionally, we investigated parents and siblings of 100 of these patients. All four parental haplotypes were established in each family (n = 400), and transmission disequilibrium tests were performed. Surprisingly, our results did not support the hypothesis of a unique susceptibility gene being shared by all MHC susceptibility haplotypes. On HLA-DR1 and -DR7-positive haplotypes IGAD1 mapped to the class II region, whereas on haplotypes carrying HLA-DR3 the susceptibility locus mapped to the telomeric end of the class III region, as reported previously. Our results show how, in complex diseases, individuals may be affected for different genetic reasons and a single linkage signal to a region of a chromosome may actually be the result of disease-predisposing alleles in different linked genes in different pedigrees.

Alleles↗
PubMed2005

Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters.

Genetic variations in drug metabolizing enzymes and targets are established determinants of adverse drug reactions and interactions, but less is known about the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a distinctive pattern of tissue expression and substrate specificity. Together, these five transporters play important roles in the disposition and elimination of drugs and other organic anions, and in maintenance of blood-tissue barriers, as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, corresponding to a human condition known as Dubin-Johnson syndrome (DJS). Naturally occurring mutations in MRP/ABCC-related drug transporters have been reported, some of which are non-synonymous single nucleotide polymorphisms. The consequences of the resulting amino acid changes can sometimes be predicted from in vitro site-directed mutagenesis studies or from knowledge of mutations of analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of sequence variants and haplotype analysis, together with in vitro biochemical validation assays and pharmacological studies in knockout animals, should make it possible to determine how genetic variation in the MRP-related transporters contributes to the range of responses to drugs and chemicals observed in different human populations.

Adenosine Triphosphate↗
PubMed2005

Molecular characterization of Korean Bacillus anthracis isolates by amplified fragment length polymorphism analysis and multilocus variable-number tandem repeat analysis.

We analyzed the genetic relationships and molecular characteristics of 34 Bacillus anthracis isolates from soil and clinical samples in various regions of Korea and 17 related Bacillus species, using the amplified fragment length polymorphism (AFLP) and multilocus variable-number tandem repeat (MLVA) approaches. Triplicate AFLP profiles of these strains showed high reproducibility and identified 376 polymorphisms. AFLP phylogenetic analysis of B. anthracis isolates showed a high level of similarity, 0.93, and this monomorphic fragment profile proved to be useful to differentiate B. anthracis strains from other Bacillus species. The B. cereus group was separated from other Bacillus species at a level of similarity of 0.68. Among them, some B. cereus strains showed genetic interspersion with B. thuringiensis strains. The evolutionary pattern of nucleotide differences among B. anthracis strains with the eight MLVA markers showed nine MLVA types. Three MLVA types, M1 to M3, were pathogenic B. anthracis isolates and were assigned as new genotypes belonging to the A4 and B3 clusters, compared with 89 genotypes deduced from previous data. This indicates that differences in cluster prevalence and distribution may be influenced more by MLVA markers on two plasmids loci and human activity. Consequently, we suggest that the novel MLVA type may represent significant evidence for historic adaptation to environmental conditions of the Asian continent, particularly Korea. Therefore, MLVA techniques may be available for molecular monitoring on anthrax-release-related bioterrorism and further study is required for the continuous epidemiological study of variable anthrax collections.

Animals↗
PubMed2006

[Advances in high-density whole genome-wide single nucleotide polymorphism array in cancer research].

A single nucleotide polymorphism (SNP) is the most common type of genetic variation, and millions of SNPs have been documented so far. Because of dense distribution of SNPs across the genome, SNPs are viewed as ideal markers for research use in the post-genomic era. The application of the high-density whole genome-wide SNP array not only leads to more rapid, economical, and high throughput genotyping but also makes the investigation of the genetic variety or change in global patterns possible. The SNP array will be widely used in various research fields, such as large-scale genome-wide linkage and association studies to discover susceptibility genes in cancer, and loss of heterozygosity analysis to discover tumor suppressor genes and tumor molecular markers, and so on.

Genetic Predisposition to Disease↗
PubMedDate not supplied

Minisequencing on functionalised self-assembled monolayer as a simple approach for single nucleotide polymorphism analysis of cattle.

We have developed a genetic barcode module, based on a parallel sorting facility of single nucleotide polymorphism for secure individual identification of cattle. Biotinylated allele-specific oligonucleotides were immobilized onto the predefined spots of streptavidin tethered self-assembled monolayers with long chain alkanethiols on biochips. The target DNAs for hybridization and subsequent on-chip minisequencing were produced by multiplex PCR method. After enzymatic extension, only the moiety-modified dideoxynucleotide triphosphate, when coupled to its complementary target sequence, could be detected by the corresponding antibody to the moiety in a specific and sensitive manner. The database SNPZoo was developed for storage of the sequence information consisting of cytosine/thymidine patterns This SNP chip system can further be used in the detection of any replaceable point mutations occurring in the human and animal genes.

Animals↗
PubMed2003

Polymorphism of genes encoding SOS polymerases in natural populations of Escherichia coli.

High fidelity replicative DNA polymerases can be blocked during DNA replication by various base damages, which represents a potentially lethal event. Escherichia coli possesses three DNA polymerases, PolII, PolIV and PolV, that can continue replication over such lesions in template DNA, thus allowing for cell survival. Genes coding for these enzymes, polB, dinB, and umuCD respectively, belong to the stress-inducible SOS regulon. We have analyzed the patterns of nucleotide sequence variability of genes encoding for three SOS polymerases from E. coli natural isolates in order to identify the nature of selective forces that determine their evolution. The frequency of inferred inter-strain recombination events, and the frequency of synonymous and non-synonymous base substitutions within these genes do not deviate significantly from those observed for the control group composed of 2 genes coding for DNA polymerases PolI and PolIII and 10 metabolic genes. This suggests that the loci coding for SOS polymerases are subject to selective pressure for the maintenance of their function and specificity. The fact that genes coding for translesion-synthesis (TLS) polymerases, particularly dinB and umuC homologs, have been conserved during evolution and the present analysis suggest that their activity is essential for the cellular survival and fitness.

Bacterial Proteins↗
PubMed2006

Molecular biology on the ICU. From understanding to treating sepsis.

Mounting evidence suggests that beside well established factors, such as virulence of pathogens or site of infection, individual differences in disease manifestation are a result of the genetic predisposition of the patient on an Intensive Care Unit (ICU). Specific genetic factors might not only predict the risk to acquire severe infections but also to develop organ dysfunction or ultimately to die. Thus, the advent of molecular techniques allowing screening for a wide variety of genetic factors, such as single nucleotide polymorphisms in genes controlling expression of important mediator systems in patients as well as their purposeful targeting in animal models of sepsis, are revolutionizing understanding of pathophysiology in the critically ill. Molecular tools are about to challenge ''state-of-the-art'' diagnostic tests such as blood culture as they not only increase sensitivity but dramatically reduce time requirements to identify pathogens and their resistance patterns. Similarly, knowledge of genetic factors might in the near future help to identify ''patients at risk'', i.e. those with a high likelihood to develop organ dysfunction or to guide therapeutic interventions in particular regarding resource-consuming and/or expensive therapies (''theragnostics''). While therapeutic options in molecular intensive care medicine, such as stem cells in the treatment of organ failure or therapeutic gene transfer are possible along the road and might become an option in the future, recombinant DNA technology has already a well defined role in the production of recombinant human proteins from insulin to activated protein C.

Adult↗
PubMed2001

Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations.

Variation in the angiotensinogen gene, AGT, has been associated with variation in plasma angiotensinogen levels. In addition, the T235M polymorphism in the AGT product is associated with an increased risk of essential hypertension in multiple populations, making AGT a good example of a quantitative-trait locus underlying susceptibility to a common disease. To better understand genetic variation in AGT, we sequenced a 14.4-kb genomic region spanning the entire AGT and identified 44 single-nucleotide polymorphisms (SNPs). Forty-two SNPs were observed both in 88 white and in 77 Japanese unselected subjects. Six major haplotypes accounted for most of the variation in this region, indicating less allelic complexity than in many other genomic regions. Although the two populations were found to share all of the major AGT haplotypes, there were substantial differences in haplotype frequencies. Pairwise linkage disequilibrium (LD), measured by the D', r(2), and d(2) statistics, demonstrated a general pattern of decline with increasing distance, but, as expected in a small genomic region, individual LD values were highly variable. LD between T235M and each of the other 39 SNPs was assessed in order to model the usefulness of LD to detect a disease-associated mutation. Among the Japanese subjects, 13 (33%) of the SNPs had r(2) values >0.1, whereas this statistic was substantially higher for the white subjects (occurring in 35/39 [90%]). LD between a hypertension-associated promoter mutation, A-6G, and 39 SNPs was also measured. Similar results were obtained, with 33% of the SNPs showing r(2)>0.1 in the Japanese subjects and 92% of the SNPs showing r(2)>0.1 in the white subjects. This difference, which occurs despite an overall similarity in LD patterns in the two populations, reflects a much higher frequency of the M235-associated haplotype in the white sample. These results have important implications for the usefulness of LD approaches in the mapping of genes underlying susceptibility to complex diseases.

Angiotensinogen↗
PubMed1999

Single nucleotide polymorphism (SNP) discovery and linkage mapping of bovine cytokine genes.

Polymorphic markers at bovine gene loci facilitate the integration of cattle genetic maps with those of humans and mice. To this end, 31 single nucleotide polymorphism (SNP) markers were developed for seven bovine chemokine genes. Loci were amplified from bovine genomic DNA by the polymerase chain reaction, and candidate amplicons were sequenced to determine their identity. Amplified loci from 24 founding parents and select progeny from a beef cattle reference population were sequenced and analyzed for SNPs. SNP haplotype alleles were determined by examining segregation patterns and used to establish the locus position on the bovine linkage map. Loci for growth-related proteins (GRO3, GRO1, and GROX) were clustered with the related CXC chemokine genes, interleukin (IL) 8, and epithelial cell inflammatory protein 1, at 84 cM from the centromeric end of the bovine chromosome (BTA) 6 linkage group. Bovine loci for a cluster of IL8 receptors, a stromal cell-derived factor 1, interferon-gamma, and tumor necrosis factor-alpha were mapped at 90, 55, 59, and 34 cM, respectively, from the centromeric ends of the BTA 2, 28, 5, and 23 linkage groups. The positions of these bovine loci were compared with those of orthologous loci on the human map to refine the boundaries of conserved synteny. These seven loci provide examples of SNP development in which the efficiency was largely dependent on the availability of bovine genomic or cDNA sequence. The polymorphic nature of these SNP haplotype markers suggests that they will be useful for mapping complex traits in cattle, such as resistance to infectious disease.

Animals↗
PubMed2000

Human-chimpanzee DNA sequence variation in the four major genes of the renin angiotensin system.

The renin angiotensin system (RAS) is involved in blood pressure control and water/sodium metabolism. The genes encoding the proteins of this system are candidate genes for essential hypertension. The RAS involves four main molecules: angiotensinogen, renin, angiotensin I-converting enzyme, and the angiotensin II type 1 receptor (encoded by the genes AGT, REN, DCP1, and AGTR1, respectively). We performed a molecular screening over 17,037 bp of the coding and 5' and 3' untranslated regions of these genes, from three to six common chimpanzees. We identified 44 single-nucleotide polymorphisms (SNPs) in chimpanzee samples, including 18 coding-region SNPs, 5 of which led to an amino acid replacement. We observed common and different features at various sites (synonymous, nonsynonymous, and noncoding) within and between the four chimpanzee genes: (1) the nucleotide diversity at noncoding sites was similar; (2) the nucleotide diversity at nonsynonymous sites was low, probably reflecting purifying selection, except for the AGT gene; (3) the nucleotide diversity at synonymous sites, which was dependent on the G+C content at the third position of the codon, was high, except for the AGTR1 gene. Comparison of the chimpanzee SNPs with those previously reported for humans identified 119 sites with fixed differences (including 62 coding sites, 17 of which resulted in amino acid differences between the species). Analysis of polymorphism within species and divergence between species shed light on the evolutionary constraints on these genes. In particular, comparison of the pattern of mutation at polymorphic and fixed sites between humans and chimpanzees suggested that the high G+C content of the DCP1 gene was maintained by positive selection at its silent sites. Finally, we propose 68 ancestral alleles for the human RAS genes and discuss the implications for their use in future hypertension-susceptibility association studies.

Angiotensinogen↗