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Results for “Haplotype structures”

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PubMed1997

Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping.

Combined Factors V and VIII deficiency is an autosomal recessive bleeding disorder identified in at least 58 families comprising a number of different ethnic groups. Affected patients present with a moderate bleeding tendency and have Factor V and Factor VIII levels in the range of 5-30% of normal. The highest frequency of the mutant gene is found in Jews of Sephardic and Middle Eastern origin living in Israel with an estimated disease frequency of 1:100,000. We sought to identify the gene responsible for combined Factors V and VIII deficiency using a positional cloning approach. Of 14 affected individuals from 8 unrelated Jewish families, 12 were the offspring of first-cousin marriages. After a genome-wide search using 241 highly polymorphic short tandem repeat (STR) markers, 13 of the 14 affected patients were homozygous for two closely linked 18q markers. Patients and all available family members were genotyped for 11 additional STRs spanning approximately 11 cM on the long arm of chromosome 18. Multipoint linkage analysis yielded a maximal log of the odds (LOD) score of 13.22. Haplotype analysis identified a number of recombinant individuals and established a minimum candidate interval of 2.5 cM for the gene responsible for combined Factors V and VIII deficiency. The product of this locus is likely to operate at a common step in the biosynthetic pathway for these two functionally and structurally homologous coagulation proteins. Identification of this gene should provide new insight into the biology of Factor V and Factor VIII production.

Chromosome Mapping↗

PubMed2006

Genetic relationship of Chinese and Japanese gamecocks revealed by mtDNA sequence variation.

Cockfighting has a very long history dating back to as early as 2500 years ago in China. Cockfighting was intertwined with human cultural traditions, helped disperse chickens across the world, and influenced the subsequent breed selection. Therefore, tracing the origin of gamecocks could mirror the distribution of the cockfighting culture. In this study, we compared the available mtDNA control region sequences in Chinese and Japanese gamecocks to test the recently proposed hypothesis behind the dual origin of the Japanese cockfighting culture (from China and Southeast Asia independently). We assigned gamecock mtDNAs to different matrilineal components (or phylogenetic clades) that emerged from the phylogenetic tree and network profile, and compared the frequency differences between Chinese and Japanese gamecocks. Among the six clades (A-F) identified, Japanese gamecocks were most frequently found in clades C and D (74%, 32/43), whereas more than half of the Chinese gamecock samples (69%, 35/51) were grouped in clades A and B. Haplotypes in Japanese gamecocks assigned to clades A, B, and E were either shared with those of the Chinese samples or differed from the close Chinese types by no more than a three-mutation distance. This genetic pattern is in accordance with the proposed dual origin of Japanese gamecocks but has left room for single origin of Japanese gamecocks from China. The genetic structure of gamecocks in China and Japan might also be influenced by subsequent breed selection and conservation after the initial gamecock introduction.

Animals↗

PubMed2006

Phylogeography of the Percichthyidae (Pisces) in Patagonia: roles of orogeny, glaciation, and volcanism.

We used molecular evidence to examine the roles that vicariance mechanisms (mountain-building and drainage changes during the Pleistocene) have played in producing phylogeographical structure within and among South American fish species of the temperate perch family Percichthyidae. The percichthyids include two South American genera, Percichthys and Percilia, each containing several species, all of which are endemic to southern Argentina and Chile (Patagonia). Maximum-likelihood phylogenies constructed using mitochondrial DNA (mtDNA) control region haplotypes and nuclear GnRH3-2 intron allele sequences support the current taxonomy at the genus level (both Percichthys and Percilia form strongly supported, monophyletic clades) but indicate that species-level designations need revision. Phylogeographical patterns at the mtDNA support the hypothesis that the Andes have been a major barrier to gene flow. Most species diversity occurs in watersheds to the west of the Andes, together with some ancient divergences among conspecific populations. In contrast, only one species (Percichthys trucha) is found east of the Andes, and little to no phylogeographical structure occurs among populations in this region. Mismatch analyses of mtDNA sequences suggest that eastern populations last went through a major bottleneck c. 188 000 bp, a date consistent with the onset of the penultimate and largest Pleistocene glaciation in Patagonia. We suggest that eastern populations have undergone repeated founder-flush events as a consequence of glacial cycles, and that the shallow phylogeny is due to mixing during recolonization periods. The area of greater diversity west of the Andes lies outside the northern limit of the glaciers. mtDNA mismatch analysis of the genus Percilia which is restricted to this area suggests a long-established population at equilibrium. We conclude that patterns of genetic diversity in these South American genera have been primarily influenced by barriers to gene flow (Andean orogeny, and to a lesser extent, isolation in river drainages), and by glacial cycles, which have resulted in population contraction, re-arrangement of some watersheds, and the temporary breakdown of dispersal barriers among eastern river systems.

Animals↗

PubMed1988

Structural basis for the C4d.1/C4d.2 serologic allotypes of murine complement component C4.

The C4d.1 antigenic specificity was first defined serologically in 1959 as an H-2-associated cellular alloantigen first designated "G," later H-2.7. It was subsequently shown to be an allotype of component C4 of the C system, with the antigenic determinant carried on the C4d proteolytic fragment of the alpha-chain, thus the designation C4d.1. Alloantisera defining an antithetical Ag, C4d.2, were also prepared. Previous studies in our laboratory showed that the structural difference between the two specificities resides in a single tryptic peptide of C4d. As an efficient approach to definition of the amino acid difference(s) involved, genomic clones covering the C4d regions from two H-2 haplotypes of the C4d.1 type have been prepared and sequenced, and compared with two sequences already available for C4d.2-type molecules. The results indicate that the rather striking serologic difference between C4d.1 and C4d.2 is attributable to the single amino acid substitution of arginine in C4d.2 for glutamine in C4d.1. The substituted residue is in a highly hydrophilic region of the C4 molecule, at a position homologous to one that contributes to the Chido/Rodgers serologic difference of human C4 molecules. This substitution also determines a new Pst I site in C4d.1 strains. A HindIII restriction fragment length polymorphism between C4d.1 and C4d.2 has also been observed.

Amino Acid Sequence↗

PubMed2006

A tutorial on statistical methods for population association studies.

Although genetic association studies have been with us for many years, even for the simplest analyses there is little consensus on the most appropriate statistical procedures. Here I give an overview of statistical approaches to population association studies, including preliminary analyses (Hardy-Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association. My goal is to outline the key methods with a brief discussion of problems (population structure and multiple testing), avenues for solutions and some ongoing developments.

Genetics, Medical↗

PubMed1997

Phylogeographic structure of white oaks throughout the European continent.

Patterns of chloroplast DNA (cpDNA) variation were studied in eight white oak species by sampling 345 populations throughout Europe. The detection of polymorphisms by restriction analysis of PCR-amplified cpDNA fragments allowed the identification of 23 haplotypes that were phylogenetically ordered. A systematic hybridization and introgression between the eight species studied is evident. The levels of subdivision for unordered (GST) and ordered (NST) alleles are very high and close (0.83 and 0.85). A new statistical approach to the quantitative study of phylogeography is presented, which relies on the coefficients of differentiation GST and NST and the Mantel's test. Based on pairwise comparisons between populations, the significance of the difference between both coefficients is evaluated at a global and a local scale. The mapped distribution of the haplotypes indicates the probable routes of postglacial recolonization followed by oak populations that had persisted in southern refugia, especially in the Iberian peninsula, Italy and the Balkans. Most cpDNA polymorphisms appear to be anterior to the beginning of the last recolonization. A subset of the preexisting haplotypes have merely expanded north, while others were left behind in the south.

DNA, Chloroplast↗

PubMed2026

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Short-read sequencing cannot determine whether co-occurring variants within a cancer gene lie on the same allele (cis) or opposing alleles (trans), a distinction with direct therapeutic consequences: trans configurations confirm biallelic tumor suppressor inactivation, whereas cis configurations generate compound oncogenic alleles with enhanced activity. Among 768 patients with prostate, breast, or ovarian cancers, we used mutational signatures to nominate cryptic genomic instability cases lacking a causative biallelic event on short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%) through methylation detection, long insertion resolution, and structural variant characterization, confirming trans inactivation in every resolved tumor suppressor case. Analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, 78.7% of which exceeded the 500 bp short-read phasing limit, and long-read phasing revealed recurrent compound cis alleles in NOTCH1, PIK3CA, PDGFRB, and KIT. Haplotype phasing addresses an overlooked gap in cancer variant interpretation and warrants integration into precision oncology.

Journal Article↗

PubMed2003

Ethnic India: a genomic view, with special reference to peopling and structure.

We report a comprehensive statistical analysis of data on 58 DNA markers (mitochondrial [mt], Y-chromosomal, and autosomal) and sequence data of the mtHVS1 from a large number of ethnically diverse populations of India. Our results provide genomic evidence that (1) there is an underlying unity of female lineages in India, indicating that the initial number of female settlers may have been small; (2) the tribal and the caste populations are highly differentiated; (3) the Austro-Asiatic tribals are the earliest settlers in India, providing support to one anthropological hypothesis while refuting some others; (4) a major wave of humans entered India through the northeast; (5) the Tibeto-Burman tribals share considerable genetic commonalities with the Austro-Asiatic tribals, supporting the hypothesis that they may have shared a common habitat in southern China, but the two groups of tribals can be differentiated on the basis of Y-chromosomal haplotypes; (6) the Dravidian tribals were possibly widespread throughout India before the arrival of the Indo-European-speaking nomads, but retreated to southern India to avoid dominance; (7) formation of populations by fission that resulted in founder and drift effects have left their imprints on the genetic structures of contemporary populations; (8) the upper castes show closer genetic affinities with Central Asian populations, although those of southern India are more distant than those of northern India; (9) historical gene flow into India has contributed to a considerable obliteration of genetic histories of contemporary populations so that there is at present no clear congruence of genetic and geographical or sociocultural affinities.

Chromosomes, Human, Y↗

PubMed2003

Chloroplast DNA phylogeography reveals colonization history of a Neotropical tree, Cedrela odorata L., in Mesoamerica.

Spanish Cedar (Cedrela odorata L.) is a globally important timber species which has been severely exploited in Mesoamerica for over 200 years. Using polymerase chain reaction-restriction fragment length polymorphisms, its chloroplast (cp) DNA phylogeography was studied in Mesoamerica with samples from 29 populations in six countries. Five haplotypes were characterized, phylogenetically grouped into three lineages (Northern, Central and Southern). Spatial analysis of ordered genetic distance confirmed deviation from a pattern of isolation by distance. The geographically proximate Northern and Central cpDNA lineages were genetically the most differentiated, with the Southern lineage appearing between them on a minimum spanning tree. However, populations possessing Southern lineage haplotypes occupy distinct moist habitats, in contrast to populations possessing Northern and Central lineage haplotypes which occupy drier and more seasonal habitats. Given the known colonization of the proto-Mesoamerican peninsula by South American flora and fauna prior to the formation of the Isthmus of Panama, it seems most likely that the observed population structure in C. odorata results from repeated colonization of Mesoamerica from South American source populations. Such a model would imply an ancient, pre-Isthmian colonization of a dry-adapted type (possessing the Northern lineage or a prototype thereof), with a secondary colonization via the land bridge. Following this, a more recent (possibly post-Pleistocene) expansion of moist-adapted types possessing the Southern lineage from the south fits the known vegetation history of the region.

Cedrela↗

PubMed1990

Structurally interdependent and independent regions of allelic polymorphism in class II MHC molecules. Implications for Ia function and evolution.

Possible interactions between regions of allelic polymorphism in the alpha- and beta-chains of class II MHC molecules were examined by measuring the efficiency of surface expression and the reactivity with mAb of wild-type and recombinant A alpha A beta-chain pairs from the b, d, and k haplotypes. These studies revealed regions of polymorphism within the alpha- and beta-chains that interact with complementary regions in the other chain. Unexpectedly, almost all the variable segments of both the class II MHC alpha- and beta-chains either directly contributed to or were near sites of interchain interactions. The exception was the beta HV3 (hypervariable (HV] segment (residues 61-71), which appeared to neither participate in nor be affected by interchain interactions. This division of the MHC molecule into interacting vs independent regions of allelic structural variation suggests that mutagenesis experiments involving the beta HV3 segment can be analyzed in a straightforward manner, as such mutations appear unlikely to alter the conformation of other molecular segments. Furthermore, functions attributed to the beta HV3 segment either experimentally or by population analysis should have a high probability of transfer by beta HV3 exchange (either experimentally or evolutionarily), because epitopes assigned to this region of the molecule are not affected by sequences outside this segment. This is of special importance because of the apparent involvement of this region in defining a potential site of interaction with antigenic peptides and TCR. In contrast, almost all other variable segments of the MHC molecule appear to have the capacity to contribute to interactions involving at least one other variable segment. This suggests not only that the experimental analysis of the contributions of these regions to various functions requires a consideration of inter- and intrachain interaction, but also that the transfer of function by genetic exchange of these structurally dependent regions is unpredictable. Selection must therefore operate on these interacting HV segments in the context of the complete alpha beta heterodimer. These results support our earlier arguments for cis-co-evolution of alpha- and beta-chain polymorphism and the absence of selection for F1 (hybrid) class II molecules. Finally, asymmetries observed in the contributions of particular pairs of HV segments to the efficient expression of Ia alpha beta heterodimers provide a basis for understanding mechanistically how cis-co-evolution may have occurred.

Alleles↗

PubMed2005

Expression genetics and haplotype analysis reveal cis regulation of serine carboxypeptidase I (Cxp1), a candidate gene for malting quality in barley (Hordeum vulgare L.).

Using a cDNA array-based functional genomics approach in barley, several candidate genes for malting quality including serine carboxypeptidase I (Cxp1) were previously identified (Potokina et al. in Mol Breed 14:153, 2004). The gene was mapped as a single nucleotide polymorphism (SNP) marker on chromosome 3H using the Steptoe (feeding grade)xMorex (malting grade) mapping population. Subsequently, the relative level of Cxp1 expression was determined by real-time RT-PCR for each of the 134 progeny lines and mapped as a quantitative trait. Only one quantitative trait locus (QTL) could be identified that significantly influenced the level of the Cxp1 expression. The expressed QTL maps to the same region on chromosome 3H as does the structural gene and corresponds to a QTL for "diastatic power," one among several traits measured to assess malting quality. An analysis of 90 barley cultivars sampled from a worldwide collection revealed six SNPs at the Cxp1 locus, three of which display complete linkage disequilibrium and define two haplotypes. The Cxp1 expression level in a set of barley accessions showing haplotype I was significantly higher than that of accessions displaying haplotype II. The data provide evidence that (1) the expression of Cxp1 is regulated in cis and that (2) the level of diastatic power in the barley seed is influenced by the level of Cxp1 expression.

Cathepsin A↗

PubMed2004

Cloning and characterization of FAM13A1--a gene near a milk protein QTL on BTA6: evidence for population-wide linkage disequilibrium in Israeli Holsteins.

A cluster of genes coding for proteins of the extracellular matrix (ECM) containing sequence motifs essential for integrin-receptor interactions is located on HSA4q21 and on BTA6, within the critical region of a quantitative trait locus (QTL) affecting milk protein production. Genes within this cluster are involved in the formation of bone and lobuloalveolar structures in mammary gland and in kidney function. We cloned a bovine gene neighboring this ECM cluster, termed FAM13A1, the first member of a novel gene family (FAM13). A short predominant 5.1-kb mRNA variant capable of encoding 697 amino acids is transcribed from 18-exon orthologous genes in human and mouse. All putative protein orthologs contained a bipartite nuclear-localization signal and two coil-coiled domains. We detected two other FAM13 paralogs, C5ORF5 and FAM13C1, on HSA5q31 and HSA10q21, respectively. All FAM13 paralogs produce transcripts that are complementary to adjacent genes, suggesting that antisense transcription may regulate their functions. The structure of a longer 5.9-kb variant, FAM13A1_v2, that has an extra 7-exon putative RhoGAP domain at the N-terminus provides further clues to FAM13 function. Analysis of 400 bulls revealed a population-wide linkage disequilibrium between FAM13A1 polymorphisms and the QTL.

Amino Acid Sequence↗

PubMed2001

Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population.

Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid metabolism. We noted that a large proportion (10 of 34) of families with MSUD that were followed in our clinic were of Ashkenazi Jewish (AJ) descent, leading us to search for a common mutation within this group. On the basis of genotyping data suggestive of a conserved haplotype at tightly linked markers on chromosome 6q14, the BCKDHB gene encoding the E1beta subunit was sequenced. Three novel mutations were identified in seven unrelated AJ patients with MSUD. The locations of the affected residues in the crystal structure of the E1beta subunit suggested possible mechanisms for the deleterious effects of these mutations. Large-scale population screening of AJ individuals for R183P, the mutation present in six of seven patients, revealed that the carrier frequency of the mutant allele was approximately 1/113; the patient not carrying R183P had a previously described homozygous mutation in the gene encoding the E2 subunit. These findings suggested that a limited number of mutations might underlie MSUD in the AJ population, potentially facilitating prenatal diagnosis and carrier detection of MSUD in this group.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed2005

A mitochondrial DNA minisatellite reveals the postglacial history of jack pine (Pinus banksiana), a broad-range North American conifer.

Jack pine (Pinus banksiana Lamb.) is a broadly distributed North American conifer and its current range was covered by the Laurentian ice sheet during the last glacial maximum. To infer about the history and postglacial colonization of this boreal species, range-wide genetic variation was assessed using a new and highly variable minisatellite-like marker of the mitochondrial genome. Among the 543 trees analysed, 14 distinct haplotypes were detected, which corresponded to different repeat numbers of the 32-nucleotide minisatellite-like motif. Several haplotypes were rare with limited distribution, suggesting recent mutation events during the Holocene. At the population level, an average of 2.6 haplotypes and a mean haplotype diversity (H) of 0.328 were estimated. Population subdivision of genetic diversity was quite high with G(ST) and R(ST) values of 0.569 and 0.472, respectively. Spatial analyses identified three relatively homogeneous groups of populations presumably representative of genetically distinct glacial populations, one west and one east of the Appalachian Mountains in the United States and a third one presumably on the unglaciated northeastern coastal area in Canada. These results indicate the significant role of the northern part of the US Appalachian Mountains as a factor of vicariance during the ice age. A fourth distinct group of populations was observed in central Québec where the continental glacier retreated last. It included populations harbouring haplotypes present into the three previous groups, and it had higher level of haplotype diversity per population (H = 0.548) and lower population differentiation (G(ST) = 0.265), which indicates a zone of suture or secondary contact between the migration fronts of the three glacial populations. Introgression from Pinus contorta Dougl. var. latifolia Engelm. was apparent in one western population from Alberta. Altogether, these results indicate that the mitochondrial DNA variation of jack pine is geographically highly structured and it correlates well with large-scale patterns emerging from recent phylogeographical studies of other tree boreal species in North America.

Base Sequence↗

PubMed2005

The MHC-haplotype influences primary, but not memory, immune responses to an immunodominant peptide containing T- and B-cell epitopes of the caprine arthritis encephalitis virus Gag protein.

In this report, we describe a short peptide, containing a T helper- and a B-cell epitope, located in the Gag protein of the caprine arthritis encephalitis virus (CAEV). This T-cell epitope is capable of inducing a robust T-cell proliferative response in vaccinated goats with different genetic backgrounds and to provide help for a strong antibody response to the B-cell epitope, indicating that it may function as a universal antigen-carrier for goat vaccines. The primary immune response of goats homozygous for MHC class I and II genes showed an MHC-dependent partitioning in rapid-high and slow-low responses, whereas the memory immune response was strong in both groups, demonstrating that a vaccine based on this immunodominant T helper epitope is capable to overcome genetic differences.

Amino Acid Sequence↗

PubMed2006

A novel missense mutation in the mouse hairless gene causes irreversible hair loss: genetic and molecular analyses of Hr m1Enu.

A novel autosomal recessive mutant was produced using N-ethyl-N-nitrosourea mutagenesis. The characteristics of the mutant mice included progressive irreversible hair loss within a month of birth, wrinkled skin, and long curved nails. Linkage analysis revealed that the causative gene is linked to D14Mit193 on chromosome 14. Sequence analysis of the complete cDNA of the candidate gene, hairless (Hr), identified a homozygous G-to-T transition at nucleotide 3572, leading to the substitution of glycine by tryptophan, designated Gly960Trp. This missense mutation occurs in the vicinity of repression domain 3 of the hairless protein (HR). This allele was named Hr(m1Enu). The relative amounts of Hr mRNA and HR protein determined by real-time PCR and Western blot analyses, respectively, were slightly elevated in the mutant mice. Quantitative real-time PCR analysis revealed the increased expression of Kc1 and Vdr in the mutant mice, whereas the expression of Nrs1 and Krtap16-6 was decreased. These results suggest that the Gly960Trp substitution in HR protein in Hr(m1Enu) mice may alter the function of HR as a transcriptional corepressor.

Alleles↗

PubMed2000

Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

Base Sequence↗

PubMed2001

Novel RET mutations in Hirschsprung's disease patients from the diverse South African population.

Hirschsprung's disease (HSCR) is a common cause of intestinal obstruction in neonates with an incidence of one in 5000 live births. The disease occurs due to the absence of parasympathetic neuronal ganglia in the hindgut, resulting in irregular or sustained contraction of the affected segment. DNA samples of 40 unrelated subjects with HSCR were subjected to mutation screening of the RET (REarranged during Transfection) proto-oncogene, the major susceptibility gene for HSCR. Five novel (V202M, E480K, IVS10-2A/G, D771N, IVS19-9C/T) and one previously described mutation (P973L) were identified. Only two of the mutation-positive patients (from different ethnic groups) displayed total colonic aganglionosis, and both were heterozygous for mutation D771N. The potential disease-causing mutations occurred in 20% of individuals, with more males (22.5% representing seven of 31 males) affected than females (12.5% representing one of eight females). This study represents the first comprehensive genetic analysis of this disease in the diverse South African population.

Black People↗