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PubMed1988

The different types of alpha-thalassemia-2: genetic aspects.

The alpha-thal-2 haplotype is the most common cause of alpha-thal and is found in a great many of the world's populations. It is most commonly due to the deletion of a single alpha-globin structural gene, and the deletion of a single alpha locus using gene mapping methods provides objective diagnostic evidence for this haplotype. Seven varieties of nondeletion syndromes have also been described, but these seem to be responsible for a small minority of alpha-thal in all populations studied. Detailed structural analyses of the deletional types have revealed that they were caused by a wide variety of DNA recombinant events, the racial difference of which remain poorly understood.

Humans↗

PubMed2002

Minimum-recombinant haplotyping in pedigrees.

This article presents a six-rule algorithm for the reconstruction of multiple minimum-recombinant haplotype configurations in pedigrees. The algorithm has three major features: First, it allows exhaustive search of all possible haplotype configurations under the criterion that there are minimum recombinants between markers. Second, its computational requirement is on the order of O(J(2)L(3)) in current implementation, where J is the family size and L is the number of marker loci under analysis. Third, it applies to various pedigree structures, with and without consanguinity relationship, and allows missing alleles to be imputed, during the haplotyping process, from their identical-by-descent copies. Haplotyping examples are provided using both published and simulated data sets.

Algorithms↗

PubMed2005

Signature of an early genetic bottleneck in a population of Moroccan sardines (Sardina pilchardus).

Fishery assessment models meant to determine sustainability of commercial marine fish failed to predict recent stock collapses due to overexploitation. One flaw of assessment models is that they strongly rely on catch and age-composition statistics, but largely ignore the genetic background of the studied populations. We examined population genetic structure of sardine (Sardina pilchardus) in the centraleastern and northeastern Atlantic Ocean and Mediterranean Sea to aid fishery management of this heavily fished small pelagic species. We found that sardine has a striking mitochondrial control region, and sequenced a fragment of 387 bp of its 5'-end in 261 individuals collected off the coasts of Morocco (Dakhla, Tantan, Safi, Larache, and Nador), Portugal (Quarteira), Spain (Pasajes, Barcelona), and Greece (Kavala). High levels of haplotypic diversity rendered a rather unresolved NJ phylogeny. The recovered tree had no phylogeographic structuring except for the clustering of 13 individuals of Safi. In contrast, individuals grouped together according to the presence or absence of a 13-bp insertion in the sequence. Phi(ST) pairwise comparisons and molecular variance analyses supported genetic differentiation between the population of Pasajes (Bay of Biscay), and those of the Mediterranean Sea and Moroccan coast, with a contact zone around the Strait of Gibraltar. This result confirms the existence of two subspecies, S. pilchardus pilchardus and S. pilchardus sardina that were previously identified based on meristics and morphometry. Mismatch distribution analysis showed that sardine populations are expanding since the Pleistocene. Surprisingly, the population of Safi showed strong and statistically significant levels of genetic differentiation that could be related with isolation and genetic drift. Comparative analysis of the Safi population versus the rest including mismatch distributions, and a Bayesian skyline plot suggest that the Safi population likely underwent an early genetic bottleneck. The genetic singularity of the Safi population could have been responsible for the historical collapse of this sardine stock in the 1970s.

Animals↗

PubMed2000

Phylogenetic divergence in leatherside chub (Gila copei) inferred from mitochondrial cytochrome b sequences.

We examined intra-specific phylogenetic relationships in leatherside chub, Gila copei. The complete mitochondrial (mt) cytochrome b gene (1140 bp) was sequenced for 30 individuals from 10 populations that span the geographical distribution of this species. Traditional phylogenetic analyses revealed two deeply divergent and evolutionarily distinct mtDNA clades that are geographically separated in northern and southern drainage basins. Interpopulation sequence variation between clades ranged from 7.7 to 8.1%. The northern clade was genetically more similar and phylogenetically more closely related to the selected out-group Lepidomeda m. mollispinus than to the southern clade, suggesting that the taxonomy of this species may require revision. Sequence variation among populations within clades ranged from 0 to 0.3% in the north and from 0 to 0.7% in the south. Statistical parsimony was used to construct phylogenetic networks of haplotypes within clades. Nested clade analysis revealed that geographical fragmentation has played an important role in genetic structuring within northern and southern clades.

Animals↗

PubMed2003

Population genetics of the endangered Knysna seahorse, Hippocampus capensis.

The evolutionary history of the endangered Knysna seahorse, Hippocampus capensis, and the extent of gene flow among its three known populations, were investigated using 138 mitochondrial DNA control region sequences. Similarly high levels of genetic diversity were found in two of the populations (Knysna and Keurbooms Estuaries), whereas diversity in the third population (Swartvlei Estuary) was lower. Although most haplotypes are shared between at least two populations, based on the haplotype frequency distributions the three assemblages constitute distinct management units. The extant population structure of H. capensis suggests that the Knysna seahorse originated in the large Knysna Estuary. The presence of seahorses in the two smaller estuaries is either the result of a vicariance event at the beginning of the present interglacial period, colonization of the estuaries via the sea, or a combination of the two.

Animals↗

PubMed1995

Haplotype test reveals departure from neutrality in a segment of the white gene of Drosophila melanogaster.

Restriction map studies previously revealed extensive linkage disequilibria in the transcriptional unit of the white locus in natural Drosophila melanogaster populations. To understand the causes of these disequilibria, we sequenced a 4722-bp region of the white gene from 15 lines of D. melanogaster and 1 line of Drosophila simulans. Statistical tests applied to the entire 4722-bp region do not reject neutrality. In contrast, a test for high-frequency haplotypes ("Haplotype test") revealed an 834-bp segment, encompassing the 3' end of intron 1 to the 3' end of intron 2, in which the structure of variation deviates significantly from the predictions of a neutral equilibrium model. The variants in this 834-bp segment segregate as single haplotype blocks. We proposed that these unusually large haplotype blocks are due to positive selection on polymorphisms within the white gene, including a replacement polymorphism, Arg-->Leu, within this segment.

ATP-Binding Cassette Transporters↗

PubMed2007

Genetic polymorphisms and haplotypes of DNA repair genes in childhood acute lymphoblastic leukemia.

BACKGROUND: Polymorphisms of DNA repair genes can alter protein structure and may impair DNA repair capacity. Defects in repairing damaged DNA lead to genetic instability and carcinogenesis. This study was performed to evaluate the effect of the polymorphisms of DNA repair genes on risk of childhood acute lymphoblastic leukemia (ALL). PROCEDURES: We genotyped polymorphisms of X-ray repair cross-complimenting group 1 (XRCC1) codon 194 (Arg to Trp), 280 (Arg to His) and 399 (Arg to Gln), and xeroderma pigmentosum group D (XPD) codon 312 (Asp to Asn) and 715 (Lys to Gln) in 108 children with ALL and 317 healthy controls using PCR-RFLP method. The allele, genotype, and haplotype frequencies of these polymorphisms were compared between cases and controls using Chi-square or Fisher's exact test. PHASE computer software was used to analyze estimated haplotypes of the XRCC1 and XPD polymorphisms. RESULTS: The frequency of XRCC1 194Trp allele in patients was significantly lower than that in controls (odds ratio (OR) 0.67; 95% confidence interval (CI), 0.47-0.97). Individuals with XRCC1 194 Trp/Trp genotype had a significantly reduced risk of ALL (OR 0.22; 95% CI, 0.05-0.96). The frequency of the XRCC1 haplotype B (194Trp-280Arg-399Arg) was significantly lower in children with ALL when compared to controls. The XRCC1 399Gln allele was associated with a significantly increased risk of ALL (OR 1.67; 95% CI, 1.20-2.33). The frequency of the XRCC1 haplotype C (194Arg-280Arg-399Gln) was significantly higher in patients. There was no difference of allele frequencies of the XRCC1 280 (Arg to His), XPD 312 (Asp to Asn), or XPD 715 (Lys to Gln) between cases and controls. CONCLUSION: The XRCC1 194Trp allele and haplotype B showed a protective effect against development of childhood ALL. In contrast, individuals with the XRCC1 399Gln allele and haplotype C were associated with increased risk for this disease.

Adolescent↗

PubMed1990

Polymorphism of the human complement component C4.

The genes encoding the two C4 isotypes, C4A and C4B, lie 10 kb apart in the class III region of the human major histocompatibility complex. The two isotypes exhibit extensive structural polymorphism. Characterisation of a number of C4A and C4B alleles has established the pattern of polymorphism in C4 and this has provided a structural basis for the observed functional and serological differences between the C4 isotypes. An intriguing feature in the genetics of C4 is the unusually high frequency of null alleles forming half null C4A and C4B haplotypes. Duplication of one of the loci has also been recognised. In addition the genes can differ in size due to the presence or absence of a large intron near the 5' end of the genes. These differences in gene size and gene number can be observed directly on different haplotypes using pulsed field gel electrophoresis.

Alleles↗

PubMed1986

T cell clones specific for an amphipathic alpha-helical region of sperm whale myoglobin show differing fine specificities for synthetic peptides. A multiview/single structure interpretation of immunodominance.

The T cell response to sperm whale myoglobin in the H-2d haplotype has been shown to be largely focused on a limited region around glutamic acid 109 recognized in association with I-Ad. T cell clones 9.27 and 1.2 have been previously (4, 5) shown to reflect this specificity and MHC restriction. In this study we have used a panel of synthetic peptides from the region 102-118 of myoglobin to characterize the specificities of these representative clones. The segment from 106-118 was found to represent a consensus region for recognition by both clones. However, we saw significant differences between clones in the hierarchy of responsiveness to peptides within the panel. In as much as the peptide and the I-Ad molecule remain constant, these differences derive from differences in how each T cell receptor interacts with the antigen. This peptide segment is an amphipathic alpha helix in native myoglobin, meaning that one side is hydrophobic and the other hydrophilic. It is one of the prototype cases that led us to find that amphipathic helices constitute the majority of immunodominant sites recognized by helper T cells (1). It is likely that the peptide will refold into an amphipathic helix stabilized by the interface at the surface of the presenting cell. When such secondary conformation is considered, these data are consistent with a model of multiple T cell specificities arising from multiple views of a single antigen conformation at a single Ia-binding site and do not require postulation of multiple conformations or binding sites. Additionally, the finding of distinct specificities suggests that the immunodominance of this site depends not on the dominance of a single clone, but on the focusing of a polyclonal response on a single region of the molecule in association with I-Ad. The immunodominance of this particular region of the protein may thus depend on intrinsic features of the site, such as potential to form an amphipathic helix, as well as extrinsic factors such as binding properties of the I-A molecule.

Amino Acid Sequence↗

PubMed2000

Biogeography of a southern hemisphere freshwater fish: how important is marine dispersal?

Galaxias maculatus is one of the world's most widely distributed freshwater fish. This species has a marine-tolerant juvenile phase, and a geographical range extending through much of the southern hemisphere. We conducted phylogeographic analyses of 163 control region haplotypes of G. maculatus, including samples from New Zealand (five locations), Tasmania (one location) and Chile (one location). A lack of genetic structure among New Zealand samples suggests that marine dispersal facilitates considerable gene flow on an intra-continental scale. The discovery of a Tasmanian-like haplotype in one of 144 New Zealand samples indicates that inter-continental marine dispersal occurs but is insufficient to prevent mitochondrial DNA differentiation among continents. The sister relationship of Tasmanian and New Zealand clades implies that marine dispersal is an important biogeographical mechanism for this species. However, a vicariant role in the divergence of eastern and western Pacific G. maculatus cannot be rejected.

Animals↗

PubMed1983

Several mechanisms can account for defective E alpha gene expression in different mouse haplotypes.

The murine Ia antigens, encoded by the I region of the major histocompatibility complex, are cell-surface glyco-proteins (consisting of alpha and beta polypeptides) thought to be involved in the control of immune responsiveness. Mice of haplotypes b, s, q, and f fail to express one of the Ia antigen complexes, the E complex, on the cell surface. We have attempted to determine at the molecular level how such a defect (or defects) might be generated. By using I-region E alpha and A alpha gene probes for analyses of RNA and DNA structure, it was possible to conclude that at least three mechanisms can operate. Mice of haplotypes b and s bear a deletion in the E alpha gene, f haplotype mice synthesize predominantly an E alpha mRNA of aberrant size, and mice of the q haplotype seem to have a defect in RNA processing or a problem with mRNA stability, or both.

Animals↗

PubMed1999

[Characterization of a novel wild-type t(wMPI) haplotype of the house mouse (Mus domesticus L.) from Peru].

Data on molecular genetic analysis of the novel wild-type twMP1 haplotype found in a population of Mus domesticus from Peru are presented. Complementation attribution of the novel haplotype as well as fertility of heterozygotes and transmission ratio distortion (TRD) of the t-carrying chromosome in the progeny of the heterozygous males were studied. Molecular analysis was carried out by means of blot hybridization with the four t-specific probes (Tu48, Tu66, Tu119, and Tu122). Comparison of the results obtained with the data on the structure and properties of the t complexes permitted conclusion on the complete lethality of the haplotype described.

Animals↗

PubMed2001

Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma.

PURPOSE: To investigate CYP1B1 gene mutations in Japanese patients with primary congenital glaucoma (PCG). METHODS: Sixty-five unrelated Japanese patients with PCG were screened by PCR-single-strand conformational polymorphism (SSCP) analysis followed by direct sequencing. No patients were offspring of consanguineous marriages, a common occurrence among patients in previous reports. PCG haplotypes were constructed with intragenic polymorphisms in affected individuals. Three-dimensional atomic structures of human CYP1B1 and four mutant CYP1B1 sequences representing missense mutations were assembled using homology modeling and were regularized by an energy-minimization procedure. RESULTS: Eleven novel mutations, including seven definite and four probable mutations, were detected in 13 (20%) of the 65 unrelated patients. Of the seven definite mutations, three were predicted to truncate the CYP1B1 open reading frame. The other four were missense mutations (Asp192Val, Ala330Phe, Val364Met, and Arg444Gln), all located in conserved core structures determining proper folding and heme-binding ability of cytochrome P450 molecules. Molecular modeling demonstrated that two of four mutations in positions 330 and 364 were structurally neutral, but Arg444Gln caused significant structural change. Of the four probable mutations, three were missense (Val198Ile, Val320Leu, and Glu499Gly); the other was a base substitution in the noncoding region of exon 1. CONCLUSIONS: The 11 varied CYP1B1 mutations found in 13 unrelated Japanese patients with sporadic occurrence of PCG represent an allelic heterogeneity and may be unique to a specific population.

Amino Acid Sequence↗

PubMed2003

Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16.

Polymicrogyria is a common malformation of cortical development characterized by an excessive number of small gyri and abnormal cortical lamination. Multiple syndromes of region-specific bilateral symmetric polymicrogyria have been reported. We previously have described two families with bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive syndrome that we mapped to a locus on chromosome 16q12-21. Here, we extend our observations to include 19 patients from 10 kindreds, all linked to the chromosome 16q locus, allowing us to define the clinical and radiological features of BFPP in detail. The syndrome is characterized by global developmental delay of at least moderate severity, seizures, dysconjugate gaze, and bilateral pyramidal and cerebellar signs. Magnetic resonance imaging demonstrated symmetric polymicrogyria affecting the frontoparietal regions most severely, as well as ventriculomegaly, bilateral white matter signal changes, and small brainstem and cerebellar structures. We have refined our genetic mapping and describe two apparent founder haplotypes, one of which is present in two families with BFPP and associated microcephaly. Because 11 of our patients initially were classified as having other malformations, the syndrome of BFPP appears to be more common than previously recognized and may be frequently misdiagnosed.

Adolescent↗

PubMed1989

HLA and insulin gene associations with IDDM.

The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene.

Child↗

PubMed2005

A second look at mitochondrial DNA variability in European anchovy (Engraulis encrasicolus): assessing models of population structure and the Black Sea isolation hypothesis.

Genetic architectures of marine fishes are generally shallow because of the large potential for gene flow in the sea. European anchovy, however, are unusual among small pelagic fishes in showing large differences among sub-basins and in harbouring two mtDNA phylogroups ('A' & 'B'), representing 1.1-1.85 million years of separation. Here the mtDNA RFLP dataset of Magoulas et al. [1996, Mol. Biol. Evol. 13: 178-190] is re-examined to assess population models accounting for this subdivided population structure and to evaluate the zoogeographical origins of the two major phylogroups. Haplotype and nucleotide diversities are highest in the Ionian Sea and lowest in the Aegean and Black seas. However, this gradient is absent when 'A' and 'B' haplotypes are examined separately. Neither the self-sustaining nor the basin population models adequately describe anchovy population behaviour. Tests for neutrality, mismatch and nested clade analyses are concordant in depicting recent expansions of both phylogroups. Unimodel mismatch distributions and haplotype coalescences dating to the last (Eemian) interglacial ('B') and the Weichselian pleniglacial period ('A') indicate separate colonizations of the Mediterranean Basin. Phylogroup 'A' is unlikely to have arisen through continuous long-term isolation in the Black Sea because of climate extremes from displaced subpolar weather systems during the ice ages. Ancestors of both groups appear to have colonized the Mediterranean from the Atlantic in the late Pleistocene. Hence, zoogeographic models of anchovy in the Mediterranean must also include the eastern (and possibly southern) Atlantic.

Animals↗

PubMed1984

A nonpolymorphic class I gene in the murine major histocompatibility complex.

DNA sequence analysis of a class I gene (Q10), which maps to the Qa2,3 locus in the C57BL/10 (H-2b haplotype) mouse, reveals that it is almost identical to a cDNA clone (pH16) isolated from a SWR/J (H-2q haplotype) mouse liver cDNA library. Exon 5, in particular, has an unusual structure such that a polypeptide product is unlikely to be anchored in the cell membrane. Our findings suggest that the two sequences are derived from allelic class I genes, which are nonpolymorphic, in contrast to H-2K allelic sequences from the same mice, and they may encode liver-specific polypeptides of unknown function. Our previous studies indicate that the Q10 gene is a potential donor gene for the generation of mutations at the H-2K locus by inter-gene transfer of genetic information. Thus the lack of polymorphism in class I genes at the Q10 locus implies either that they are not recipients for such exchanges or that selective pressure prevents the accumulation of mutations in genes at this locus.

Alleles↗

PubMed1993

The immunoglobulin kappa locus-or-what has been learned from looking closely at one-tenth of a percent of the human genome.

The immunoglobulin kappa locus and its immediate surroundings, which are described in the present report, comprise 3 Mb of DNA, i.e., 0.1% or one per mill of the 3000 Mb of the human genome. Based on the work of our group during the past 12 years, we can now (1) depict in much detail the structure of the kappa locus with its 76 V kappa genes and pseudo genes, five J kappa elements and one C kappa gene; (2) specify the size of the germ-line repertoire of kappa light chains, which is one of the sources of the practically unlimited antibody diversity; (3) assign the known transcription products (studied as cDNAs) and kappa proteins to certain germ-line V kappa genes and attribute the differences in sequences to hypermutation and, to a lesser extent, to allelic variation; (4) analyze the hypermutation patterns which may contribute to the understanding of this enigmatic process; (5) describe the V kappa-J kappa rearrangements for half of the V kappa genes by a deletion mechanism and for the other half by a mechanism involving inversions of Mb-sized (i.e., 0.5 mm long) DNA fragments; (6) define various regulatory and other conserved sequence elements; (7) get clues as to the variation of the structure of the kappa locus in different individuals and populations, including a haplotype with only half the number of V kappa genes; (8) interpret many aspects of the evolution of the kappa locus in terms of duplications, insertions, deletions and gene conversions; (9) attribute the formation of the 24 V kappa orphons (i.e., genes outside the locus), whose sequences were determined, to pericentric inversions and other transposition processes; (10) answer a series of questions of biomedical interest; and (11) contribute 12.5 Mb of restriction maps, 1.8 Mb of clones and 250 kb of sequences to the elucidation of the human genome.

Animals↗