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PubMed1985

Hereditary thrombosis in a Utah kindred is caused by a dysfunctional antithrombin III gene.

Maximum likelihood analysis of linkage between antithrombin III (ATIII) DNA polymorphisms and ATIII deficiency in a large Utah kindred suggests that thrombotic disease in this family is caused by a dysfunctional ATIII gene. ATIII-deficient family members were identified on the basis of: (1) reduced anticoagulant activity and (2) the presence of an electrophoretically abnormal inhibitor molecule in their plasmas. Affected individuals have two copies of the ATIII structural gene, and both alleles appear normal at the resolution of whole genome Southern blotting. However, family studies revealed statistically significant cosegregation of ATIII-deficiency trait and a particular ATIII DNA polymorphism haplotype (lod = 3.35; theta = 0.0); this result is consistent with the presence of a dysfunctional ATIII gene on a chromosome of the +, S haplotype.

Alleles↗
PubMed1997

Differential structuring of human populations for homologous X and Y microsatellite loci.

The global pattern of variation at the homologous microsatellite loci DYS413 (Yq11) and DXS8174 and DXS8175 (Xp22) was analyzed by examination of 30 world populations from four continents, accounting for more than 1,100 chromosomes per locus. The data showed discordant patterns of among- and within-population gene diversity for the Y-linked and the X-linked microsatellites. For the Y-linked polymorphism, all groups of populations displayed high FST values (the correlation between random haplotypes within subpopulations, relative to haplotypes of the total population) and showed a general trend for the haplotypes to cluster in a population-specific way. This was especially true for sub-Saharan African populations. The data also indicated that a large fraction of the variation among populations was due to the accumulation of new variants associated with the radiation process. Europeans exhibited the highest level of within-population haplotype diversity, whereas sub-Saharan Africans showed the lowest. In contrast, data for the two X-linked polymorphisms were concordant in showing lower FST values, as compared with those for DYS413, but higher within-population variances, for African versus non-African populations. Whereas the results for the X-linked loci agreed with a model of greater antiquity for the African populations, those for DYS413 showed a confounding pattern that is apparently at odds with such a model. Possible factors involved in this differential structuring for homologous X and Y microsatellite polymorphisms are discussed.

Female↗
PubMed2024

Phased telomere-to-telomere reference genome and pangenome reveal an expansion of resistance genes during apple domestication.

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Earlier versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the apple's highly heterozygous genome, which impeded advances in genetic studies and breeding programs. In this study, we assembled a haplotype-resolved telomere-to-telomere (T2T) reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on 12 assemblies from wild and cultivated species to investigate the dynamic changes of functional genes. Our results revealed the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Our analyses also demonstrated a higher prevalence of different types of resistance gene analogs (RGAs) in cultivars than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR, NB-ARC-LRR, and CC-NB-ARC-LRR genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding.

Malus↗
PubMed1997

Population structure and seasonal movements of narwhals, Monodon monoceros, determined from mtDNA analysis.

We determined the nucleotide sequence of the first 287 base pairs in the mitochondrial control region from 74 narwhals, Monodon monoceros, collected in the North-west Atlantic. We detected four polymorphic sites that defined five haplotypes, two of which were found in single specimens. The same DNA sequence was characterized in an additional 353 specimens by digestion with two restriction endonucleases. In this manner each specimen could be assigned to one of the three most common haplotypes. The nucleotide diversity for the total sample (as well as the sequenced subset) was estimated as 0.0017 and pairwise genetic distances between haplotypes ranged from 0.0035-0.0070. The low nucleotide diversity and the low average pairwise genetic distance between haplotypes suggest a recent expansion in abundance from a small founding population. Despite the low degree of variation, frequencies of the common haplotypes differed markedly between areas. The results indicate isolation, even between geographically close areas, as well as fidelity to specific summer and autumn feeding grounds. Heterogeneity within a presumed single breeding ground suggests mixing of pods with different haplotypic composition.

Animals↗
PubMed2006

Phylogeography and population structure of thornback rays (Raja clavata L., Rajidae).

The phylogeography of thornback rays (Raja clavata) was assessed from European waters, using five nuclear microsatellite loci and mitochondrial cytochome b sequences. Strong regional differentiation was found between the Mediterranean basin, the Azores and the European continental shelf. Allelic and haplotype diversities were high in Portuguese populations, consistent with the existence of a refugium along the Iberian Peninsula. Unexpectedly, high diversity was also found in the English Channel/North Sea area. The lowest genetic diversity was found in the Black Sea. Populations sampled from the Mediterranean, Adriatic and Black Seas were characterized by a single mitochondrial haplotype. This haplotype was also the most ancestral and widespread outside of the Mediterranean basin except for the Azores. Populations from the Azores were dominated by a second ancestral haplotype which was shared with British populations. Results from multidimensional scaling, amova and nested clade analysis indicate that British waters are a secondary contact zone recolonized from at least two refugia--one around the Iberian Peninsula and one possibly in the Azores. Links to a potential refugium known as the Hurd Deep, between Cornwall and Brittany, are discussed. Finally, a historical demographic analysis indicates that thornback ray populations started to expand between 580,000 and 362,000 years ago, which suggests that the Last Glacial Maximum (20,000 years ago) had mainly affected the distribution of populations rather than population size.

Animals↗
PubMed1999

Sequence variation in the human angiotensin converting enzyme.

Angiotensin converting enzyme (encoded by the gene DCP1, also known as ACE) catalyses the conversion of angiotensin I to the physiologically active peptide angiotensin II, which controls fluid-electrolyte balance and systemic blood pressure. Because of its key function in the renin-angiotensin system, many association studies have been performed with DCP1. Nearly all studies have associated the presence (insertion, I) or absence (deletion, D) of a 287-bp Alu repeat element in intron 16 with the levels of circulating enzyme or cardiovascular pathophysiologies. Many epidemiological studies suggest that the DCP1*D allele confers increased susceptibility to cardiovascular disease; however, other reports have found no such association or even a beneficial effect. We present here the complete genomic sequence of DCP1 from 11 individuals, representing the longest contiguous scan (24 kb) for sequence variation in human DNA. We identified 78 varying sites in 22 chromosomes that resolved into 13 distinct haplotypes. Of the variant sites, 17 were in absolute linkage disequilibrium with the commonly typed Alu insertion/deletion polymorphism, producing two distinct and distantly related clades. We also identified a major subdivision in the Alu deletion clade that enables further analysis of the traits associated with this gene. The diversity uncovered in DCP1 is comparable to that described for other regions in the human genome. The highly correlated structure in DCP1 raises important issues for the determination of functional DNA variants within genes and genetic studies in humans based on marker association.

Alu Elements↗
PubMed1993

Carrier detection in families with properdin deficiency by microsatellite haplotyping.

Human properdin deficiency is an X-linked disorder strongly predisposing to meningococcal disease which has been recorded in over 50 cases of various ethnic origins. Immunochemically, total deficiency (type I), partial deficiency (type II), and deficiency due to a dysfunctional molecule (type III) can be differentiated. It is therefore most likely that the causative molecular defects will show considerable genetic heterogeneity. Analysis of the properdin locus at Xp11.3-Xp11.23 has led to the characterization of two polymorphic (dC-dA)n.(dG-dT)n repeats located approximately 15 kb downstream from the structural gene. Three families (two Scottish Caucasoid, one Tunisian Sephardic) with seven deficient individuals were investigated immunochemically and using a nonradioisotopic polymerase chain reaction-based method for microsatellite detection. Probable and definite carriers frequently showed properdin levels which were in the normal range. No recombinants between the microsatellite loci and properdin deficiency were detected, thus allowing identification of the defective allele through the generations in all three pedigrees. Haplotyping for these highly polymorphic microsatellites in close physical linkage to the properdin gene can provide rapid and nonradioactive detection of carrier status and prenatal diagnosis without extensive sequencing analysis.

Base Sequence↗
PubMed1992

Preferential V beta gene usage and lack of junctional sequence conservation among human T cell receptors specific for a tetanus toxin-derived peptide: evidence for a dominant role of a germline-encoded V region in antigen/major histocompatibility complex recognition.

To investigate the structural and genetic basis of the T cell response to defined peptide/major histocompatibility (MHC) class II complexes in humans, we established a large panel of T cell clones (61) from donors of different HLA-DR haplotypes and reactive with a tetanus toxin-derived peptide (tt830-844) recognized in association with most DR molecules (universal peptide). By using a bacterial enterotoxin-based proliferation assay and cDNA sequencing, we found preferential use of a particular V beta region gene segment, V beta 2.1, in three of the individuals studied (64%, n = 58), irrespective of whether the peptide was presented by the DR6wcI, DR4w4, or DRw11.1 and DRw11.2 alleles, demonstrating that shared MHC class II antigens are not required for shared V beta gene use by T cell receptors (TCRs) specific for this peptide. V alpha gene use was more heterogeneous, with at least seven different V alpha segments derived from five distinct families encoding alpha chains able to pair with V beta 2.1 chains to form a tt830-844/DR-specific binding site. Several cases were found of clones restricted to different DR alleles that expressed identical V beta and (or very closely related) V alpha gene segments and that differed only in their junctional sequences. Thus, changes in the putative complementary determining region 3 (CDR3) of the TCR may, in certain cases, alter MHC specificity and maintain peptide reactivity. Finally, in contrast to what has been observed in other defined peptide/MHC systems, a striking heterogeneity was found in the junctional regions of both alpha and beta chains, even for TCRs with identical V alpha and/or V beta gene segments and the same restriction. Among 14 anti-tt830-844 clones using the V beta 2.1 gene segment, 14 unique V beta-D-J beta junctions were found, with no evident conservation in length and/or amino acid composition. One interpretation for this apparent lack of coselection of specific junctional sequences in the context of a common V element, V beta 2.1, is that this V region plays a dominant role in the recognition of the tt830-844/DR complex.

Amino Acid Sequence↗
PubMed1999

Y-STR haplotyping in two Hungarian populations.

A set of seven Y-chromosomal STR loci (DYS19, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393) with the addition of the bilocal marker DYS385 was used to generate male-specific haplotype databases for two Hungarian population samples, Caucasians from the Budapest area and Romanies from Baranya county. At the locus DYS385 three types of intermediate sized alleles were detected in six males. The presence of a (GA) dinucleotide, probably due to an (AA) deletion in the second (GAAA) repeat of the polymorphic repeat region leads to an intermediate allelle 17.2. The intermediate alleles 17.-1 and 18.-1 with the consensus repeat structure of (GAAA)17 and (GAAA)18, respectively, were found to lack a T in the same (T)7 stretch located within the 3' flanking region of each allele. The forensic efficiency values for the Romany population were significantly lower than those found in the Central Hungarian and other non-isolated Causasian populations, which may imply a possible common paternal ancestry of some haplotypes in the Romany sample. With pairwise comparisons of inter-population molecular variance, the two populations analyzed here and an Italian population sample, could be clearly distinguished using the seven monoclonal Y-STRs. A sizing precision of < or = 0.14 nucleotide standard deviation was obtained with capillary electrophoresis carried out on an ABI Prism 310 Genetic Analyzer. Objective and accurate genotyping is thus possible using an internal size standard with a high density of fragments.

Alleles↗
PubMed2006

[Haplotypes of four single nucleotide polymorphisms in caspase-8, -10 genes in Han nationality of Zhejiang province in China].

OBJECTIVE: To investigate single nucleotide polymorphisms (SNPs) and the distribution of their haplotypes in caspase-8, -10 genes in Zhejiang Han nationality in China. METHODS: PCR, denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing were used to detect the SNPs in the 2nd-5th exons of caspase-10 gene, the 8th-10th exons of caspase-8 and their flanking sequences. Expectation Maximization (EM) algorithm was used for haplotype frequencies analysis and pairwise linkage disequilibrium (LD) test. RESULTS: (1) Two SNPs, A2823G and A12799G, were identified in caspase-10 gene, located in exon 2 and exon 5 respectively. A12799G was newly found with low informativeness. Three SNPs were identified in caspase-8 gene; A43466G, G51484A and G52951A were located in exon 8, exon 9 and intron 9, respectively. They do not change the primary structure of the encoded protein. (2) Linkage equilibrium was observed between A2823G in caspase-10 gene and the three sites in caspase-8 gene. A43466G and G52951A, and G51484A and G52951A in caspase-8 gene were also in linkage equilibrium. Their coefficients of disequilibrium were near 0. Whereas strong linkage disequilibrium was observed between A43466G and G51484A, because its coefficient of disequilibrium was near 1. (3) A total of 11 haplotypes were estimated within A2823G in caspase-10 gene and three sites in caspase-8 gene. A-2823/A-43466/G-51484/G-52951 was the main haplotype with a frequency of 0.3811. A-2823/A-43466/G-51484/A-52951 was the second haplotype with a frequency of 0.2536. The polymorphism information content of their haplotypes was 0.7106. CONCLUSION: The SNPs of caspase-8, -10 genes in Han Chinese of Zhejiang could be parsed into at least three different haplotype blocks. The polymorphism information content can be improved by using haplotype analysis of several SNPs.

Alleles↗
PubMed2005

[Single nucleotide polymorphisms of HIV coreceptor CCR5 gene in Chinese Yi ethnic group and its association with HIV infection].

OBJECTIVE: To investigate the single nucleotide polymorphism (SNP) of HIV-1 coreceptor CCR5 gene in Chinese Yi ethnic group and the association between these SNPs and HIV/AIDS. METHODS: Peripheral blood samples of 102 HIV negative persons of Chinese Yi nationality, 87 males amd 15 females, aged 23 (12-37), and 68 HIV carriers, 61 males and 7 females, aged 27 (17-51). The regulatory and structural regions of the HIV coreceptor CCR5 gene were amplified from the genomic DNA by nested PCR, each of the two regions was divided into three gene fragments which were overlapped. High throughput DHPLC was used for screening of unknown mutations in each gene fragment. The PCR products showing different peak traces from wild types in DHPLC were sequenced by forward and reverse primers respectively. The sequences were analyzed with the help of Sequence Navigator software to search for SNP loci. Statistical analysis by SPSS and PPAP softwares were made to study the association between these SNPs and HIV infection. RESULTS: Five SNPs (A77G, G316A, T532C, C921T, and G668A) and a AGA deletion of the 686-688 nucleotides were discovered in the coding region of this gene in Chinese Yi ethnic group. C921T mutation was a nonsense mutation, and the other SNPs (A77G, G316A, T532C, and G668A) are sense mutation, with the amino acid changes of K26R, G106R, C178R, and R223Q. Only the frequency of R223Q allelic gene was high (0.08) but those of the others were low (less than 0.01). There was no significant difference in the allele frequency between the HIV negative and HIV positive groups (all P > 0.05). Five SNP loci (T58934G, G59029A, T59353C, G59402A, and C59653T) were found in the regulatory region of CCR5 gene with high allelic frequencies of 0.1912-0.2941. Between the HIV negative and HIV positive groups, there were no differences in the SNP loc (all P > 0.05). Statistical analysis of the association between the linkage of mutation loci with HIV infection suggested a significant difference in the haplotype frequency of T59353C-G59402A between the HIV negative and HIV positive groups of the Yi population. CONCLUSION: A high throughput screening method of detecting unknown genetic mutation DHPLC can effectively analyze the SNP of CCR5 regulatory and structural regions in Chinese Yi ethnic group.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Familial lipoid adrenal hyperplasia: genetic marker data and an approach to prenatal diagnosis.

Some of the anatomic endocrine, and genetic aspects of lipoid adrenal hyperplasia were studied in an inbred Israeli-Arab family with two affected sibs. One sib, a genetic female, presented with acute Addisonian crisis. Endocrine studies documented elevated ACTH levels and no detectable steroids of gonadal or adrenal origin. The other patient, a male pseudo-hermaphrodite, was found at autopsy to have typical lipoid adrenal hyperplasia and ectopic adrenal tissue adjacent to an intra-abdominal testicle. Complete vagina, uterus, and fallopian tubes were present in addition to the Wolffian structures. This unique observation supports the view that steroids may be necessary for Müllerian inhibitory factor to induce regression of Müllerian structures. The segregation of 27 autosomal markers was studied in one affected and five unaffected sibs. Genetic linkage to HLA, MNS, and GPT is unlikely. In addition, the affected sib is heterozygote for a haplotype of chromosome 1 which includes the Rh, Fy, PGM-1 systems. Determination of fetal gender by the combined use of ultrasonography and amniocentesis is suggested for prenatal diagnosis and improved risk counselling.

Adrenal Hyperplasia, Congenital↗
PubMed1993

Susceptibility to demyelinating polyneuropathy in plasma cell dyscrasia may be influenced by amino acid position 9 of the HLA-DR beta chain.

Fifty-five patients with plasma cell dyscrasias were investigated by genomic typing for HLA-DR and -DQ genes by restriction fragment length polymorphism, neurophysiology and for presence of anti-myelin-associated glycoprotein (MAG) antibodies. In 26 patients, a polyneuropathy (PN) of demyelinating type was established. Among these individuals, an association was found with the presence of a tryptophan amino acid residue at position 9 of the DR beta chain (P < 0.01). This position is part of the first hypervariable region of the DR beta chain, and may be of importance in determining preferential peptide-binding capacity of the HLA-DR molecule. The presence of anti-MAG antibodies in 15 out of 17 patients with an IgM M-component and demyelinating PN (14 of these 15 individuals carrying a tryptophan at position 9) supports the pathogenic role of an autoimmune response against MAG. The finding of an HLA class II association may indicate a pathogenic role of T cell immunity in this condition.

Adult↗
PubMed2005

Identification and characterization of coding single-nucleotide polymorphisms within human protocadherin-alpha and -beta gene clusters.

The human protocadherin (Pcdh) gene clusters are located on chromosome 5q31. Single-nucleotide polymorphisms (SNPs) were detected in the Pcdh-alpha and -beta variable exons, and in the Pcdh-alpha constant exon, in samples from 104 individuals. Among coding SNPs (cSNPs), nonsynonymous (amino acid exchange) SNPs were 2.2 times more common than synonymous (silent) changes in the Pcdh-alpha variable exons, but only 1.2 times more common in the Pcdh-beta variable exons. The nonsynonymous SNPs were high in the ectodomain (EC) 1 encoding region of Pcdh-alpha but not of Pcdh-beta. One 48-kb region of extensive linkage disequilibrium (LD) is reported that has two haplotypes extending from the alpha1 to alpha7 genes in the Pcdh-alpha cluster. Here we identified 15 amino acid exchanges in these two major haplotypes; therefore, the two haplotypes encode different sets of Pcdh-alpha proteins in the brain. The distribution of cSNPs was different for each EC region of Pcdh-alpha or -beta. The frequency of cSNPs was negatively correlated with the paralogous sequence diversity. These results suggested that gene conversion events in homologous regions of the Pcdh-alpha and Pcdh-beta clusters generated the cSNPs. Within the cSNPs, gene conversions were found in Pcdh-alpha4 in the major haplotype, and in Pcdh-beta9. These gene conversions were caused by the unequal crossing-over of homologous sequence regions. Thus, nonsynonymous variations in the Pcdh-alpha and -beta genes are possible contributors to the variations in human brain function.

Alleles↗
PubMed2005

Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.

Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

Amino Acid Sequence↗
PubMed2005

An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains.

Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.

5' Untranslated Regions↗