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PubMed2026

Multi-omics identification of ZFPM2 and CD44 as key candidates for testicular size in sheep.

Testicular size is a key determinant of ram fertility, yet its genetic architecture in sheep remains poorly understood. Crossbred sheep exhibit substantial testicular developmental variation and serve as ideal models for screening fertility-related genes. Here, we performed whole-genome sequencing (WGS)-based genome-wide association study (GWAS) on 115 rams, including seven crossbred populations (each derived from a distinct sire breed crossed with Hu sheep) and a purebred Hu sheep population. We identified two variants within ZFPM2, including an intronic single nucleotide polymorphism (SNP) rs421073404 and a missense SNP rs1086332841, both significantly correlated with testis weight, length, and width. Importantly, these variants exerted testis-specific effects, consistent with their weak correlation with body weight (r < 0.2). Genomic selection scans (FST and π-ratio) between rams with large (>150 g/side) and small (<75 g/side) testes revealed multiple divergent genomic regions, with prominent haplotype differentiation at the CD44 locus on chromosome 15. Notably, two linked missense variants (rs160734053 and rs414318703) in CD44 exerted opposing effects on testicular size, suggesting allelic heterogeneity at this locus. Integrative RNA-seq and ATAC-seq across 0-12 months further uncovered prepubertal stage-specific expression and chromatin accessibility patterns of ZFPM2 and CD44, providing mechanistic insights into their regulatory roles. Collectively, this study provides candidate SNPs for sheep marker-assisted selection and multi-omic evidence for dissecting the genetic basis of testicular development in ovine breeding.

Animals↗

PubMed2002

Exploiting EST databases for the development and characterization of gene-derived SSR-markers in barley (Hordeum vulgare L.).

A software tool was developed for the identification of simple sequence repeats (SSRs) in a barley ( Hordeum vulgare L.) EST (expressed sequence tag) database comprising 24,595 sequences. In total, 1,856 SSR-containing sequences were identified. Trimeric SSR repeat motifs appeared to be the most abundant type. A subset of 311 primer pairs flanking SSR loci have been used for screening polymorphisms among six barley cultivars, being parents of three mapping populations. As a result, 76 EST-derived SSR-markers were integrated into a barley genetic consensus map. A correlation between polymorphism and the number of repeats was observed for SSRs built of dimeric up to tetrameric units. 3'-ESTs yielded a higher portion of polymorphic SSRs (64%) than 5'-ESTs did. The estimated PIC (polymorphic information content) value was 0.45 +/- 0.03. Approximately 80% of the SSR-markers amplified DNA fragments in Hordeum bulbosum, followed by rye, wheat (both about 60%) and rice (40%). A subset of 38 EST-derived SSR-markers comprising 114 alleles were used to investigate genetic diversity among 54 barley cultivars. In accordance with a previous, RFLP-based, study, spring and winter cultivars, as well as two- and six-rowed barleys, formed separate clades upon PCoA analysis. The results show that: (1) with the software tool developed, EST databases can be efficiently exploited for the development of cDNA-SSRs, (2) EST-derived SSRs are significantly less polymorphic than those derived from genomic regions, (3) a considerable portion of the developed SSRs can be transferred to related species, and (4) compared to RFLP-markers, cDNA-SSRs yield similar patterns of genetic diversity.

DNA, Plant↗

PubMed1989

BKm minisatellite sequences are not sex associated but reveal DNA fingerprint polymorphisms in rainbow trout.

GATA-GACA repetitive sequences first isolated from a female snake (termed BKm sequences) and associated with sex chromosomes in some species were hybridized to DNA from rainbow trout (Salmo gairdneri). Genomic DNA was studied from three groups of rainbow trout: (i) randomly selected males and females from an outbred group, (ii) androgenetic individuals from an inbred strain, and (iii) parents and offspring of an outbred strain. Three restriction enzymes (EcoRI, HaeIII, or HinfI) were used to digest the genomic DNA. The DNA was electrophoresed in agarose gels, transferred to nylon membranes, and the GATA-GACA repetitive sequence probe was hybridized to this DNA. There was no evidence of sex-associated patterns of hybridization with the enzymes used. However, the sequences reveal DNA fingerprint polymorphisms which appear to be inherited in a stable manner.

Animals↗

PubMed1996

Nucleotide sequence and restriction fragment-length polymorphism analysis of human T-cell lymphotropic virus type II (HTLV-II) in southern Europe: evidence for the HTLV-IIa and HTLV-IIb subtypes.

Human T-cell lymphotropic virus type II (HTLV-II) has been subtyped into two major groups, IIa and IIb, according to molecular studies involving env gene sequencing. Subsequently, this retrovirus was further subclassified by examining the long terminal repeat (LTR), the most divergent genomic region. Sequence analysis and restriction fragment-length polymorphism (RFLP) applied to the LTR region identified either four or five groups within the IIa subtype (depending on the restriction enzyme sets used) and six within the IIb subtype. In this study, we analyzed the LTR sequences of 29 samples obtained from HTLV-II-infected individuals living in Spain and Italy, which included 24 injecting drug users (IDUs), three blood donors, and two subjects at risk for HIV/HTLV infection. Sequence analysis and phylogenetic analysis of 720 base pairs of the LTR performed in 10 Spanish samples showed that all of these samples belonged to IIb subtype, with a divergence of 7.5% and 1.66% compared with MoT (IIa) and NRA/G12 (IIb) isolates, respectively. RFLP analysis demonstrated the presence of the IIb 4-subtype restriction pattern in 26 samples, a IIb5-subtype pattern in one Italian IDU, and a IIa0-subtype pattern in two Italian samples (blood donors), according to W.M. Switzer's nomenclature. This is the first report of the presence of IIb5 in Southern Europe and IIa0 among Italian blood donors. RFLP correlated with nucleotide sequence and phylogenetic data obtained in this study, demonstrating the ability of the RFLP method to predict the phylogroup of HTLV-II-infected samples.

Base Sequence↗

PubMed2006

Hypervariable region structure and polymorphism of mtDNA from dental pulp and a family analysis.

Nucleotide sequences of the hypervariable region in the D-loop of mitochondrial DNA (mtDNA) were analyzed using DNA extracted from 140 old dental pulp samples. These sequences were compared with the sequence reported by Anderson et al. Nucleotide substitution in the HV1 region was identified at 77 positions. A C-to-T transition at position 16223 (C16223T) was most frequently detected (77.9%). Fourteen types of C-stretch sequence patterns were detected and the same sequence as Anderson had the highest frequency (57.9%). In the HV2 region, base transitions were identified at 56 positions. A263G was identified in all samples. Seven types of C-stretch were detected, but none had the same sequence as Anderson. In the HV3 region, base transitions were identified at 21 positions. T489C was most frequently identified (64.3%). Five types of C-stretch were detected, and the same sequence as Anderson accounted for 92.9%. The 140 samples were classified into 128 kinds by the sequence patterns of the HV region. Next, using the blood and oral mucosa epithelium from 23 subjects comprising four generations in a family line, the hereditary relationship of mtDNA was examined. All mtDNA types of the first-generation mother were infallibly inherited by the fourth generation.

Adult↗

PubMed2002

DNA sequence variation in a 3.7-kb noncoding sequence 5' of the CYP1A2 gene: implications for human population history and natural selection.

CYP1A2 is a cytochrome P450 gene that is involved in human physiological responses to a variety of drugs and toxins. To investigate the role of population history and natural selection in shaping genetic diversity in CYP1A2, we sequenced a 3.7-kb region 5' from CYP1A2 in a diverse collection of 113 individuals from three major continental regions of the Old World (Africa, Asia, and Europe). We also examined sequences in the 90-member National Institutes of Health DNA Polymorphism Discovery Resource (PDR). Eighteen single-nucleotide polymorphisms (SNPs) were found. Most of the high-frequency SNPs found in the Old World sample were also found in the PDR sample. However, six SNPs were detected in the Old World sample but not in the PDR sample, and two SNPs found in the PDR sample were not found in the Old World sample. Most pairs of SNPs were in complete linkage disequilibrium with one another, and there was no indication of a decline of disequilibrium with physical distance in this region. The average +/- SD nucleotide diversity in the Old World sample was 0.00043+/-0.00026. The African population had the highest level of nucleotide diversity and the lowest level of linkage disequilibrium. Two distinct haplotype clusters with broadly overlapping geographical distributions were present. Of the 17 haplotypes found in the Old World sample, 12 were found in the African sample, 8 were found in Indians, 5 were found in non-Indian Asians, and 5 were found in Europeans. Haplotypes found outside Africa were mostly a subset of those found within Africa. These patterns are all consistent with an African origin of modern humans. Seven SNPs were singletons, and the site-frequency spectrum showed a significant departure from neutral expectations, suggesting population expansion and/or natural selection. Comparison with outgroup species showed that four derived SNPs have achieved high (>0.90) frequencies in human populations, a trend consistent with the action of positive natural selection. These patterns have a number of implications for disease-association studies in CYP1A2 and other genes.

5' Flanking Region↗

PubMed2001

[The Rsa I and Sma I polymorphisms in the von Willebrand factor gene discrimination by hybridization with oligonucleotide arrays].

OBJECTIVE: To develop a new assay for the Rsa I and Sma I polymorphisms (single nucleotide polymorphism, SNP) in the von Willebrand factor gene detection that utilizes oligonucleotide arrays (DNA chips) on glass supports. Expoloring the association of the RsaI and SmaI polymorphisms in the von Willebrand factor gene with thrombosis in Chinese. METHODS: Allele-specific oligonucleotides are covalently immobilized on glutaradehyde derivatized glass slides in arrays. Single strand PCR product of PCR-amplified genomic DNA is fluorescently labeled by assymetric PCR with fluorescently tagged dUTP and hybridized to the support-bound oligonucleotide array. The hybridization pattern is detected by fluorescence scenning. The effect of hybridization conditions were evaluated and optimized. The method was validated by the discrimination of blinded DNA samples identified by restriction enzymes. 50 patients with thrombosis were examined by this method. RESULTS: The genotypes scored by oligonucleotide arrays assay were in 100% agreement with restriction enzymes results. The genotype distributions GG, GA, AA and CC, CT, TT of RsaI and SmaI polymorphisms of patients or controls were 4.0%, 12.0%, 84.0% and 24.0%, 44.0%, 32.0% or 1.4%, 11.8%, 86.8% and 8.8%, 57.4%, 33.8%. The allele frequencies G, A and C, T were 10.0%, 90.0% and 46.0%, 54.0% or 7.4%, 92.6% and 37.5%, 62.5%. No statistical difference in genotype distribution and allele frequencies was observed between patients with thrombosis and the control groups (all P > 0.05). CONCLUSION: A rapid and accurate method for the RsaI and SmaI polymorphisms in the von Willebrand factor gene detection, or for the analysis of single nucleotide polymorphism (SNP) has been developed using oligonucleotide arrays on glass supports. No association was observed between the Rsa I and Sma I polymorphisms in the vWF gene and thrombotic disease.

Alleles↗

PubMed2001

Papillon-Lefèvre syndrome: mutations and polymorphisms in the cathepsin C gene.

The Papillon-Lefèvre syndrome, inherited in an autosomal recessive pattern, manifests with palmoplantar keratoderma and early, destructive periodontitis. Recently, mutations in the gene encoding cathepsin C have been disclosed in a limited number of families with Papillon-Lefèvre syndrome. We have examined two multiplex families with Papillon-Lefèvre syndrome, and evaluated the gene encoding cathepsin C for mutations. The mutation detection strategy consisted of polymerase chain reaction amplification of all seven exons and flanking intronic sequences, followed by direct nucleotide sequencing. This strategy identified two missense mutations, W39S and G301S, affecting highly conserved amino acid residues within the cathepsin C polypeptide. The affected individuals were homozygotes whereas heterozygous carriers of the mutations were clinically unaffected, confirming the recessive nature of the mutations. Addition of these cathepsin C gene mutations into the expanding Papillon-Lefèvre syndrome mutation database allows further development of genotype/phenotype correlations towards understanding this severe genodermatosis.

Cathepsin C↗

PubMed2003

Molecular haplotype determination using allele-specific PCR and pyrosequencing technology.

Haplotyping of single-nucleotide polymorphisms (SNPs) is usually performed statistically by computational analysis or by time-consuming cloning techniques. Here we present a simple molecular approach for reliable haplotype determination on individual samples. The procedure is based on allele-specific PCR (AS-PCR) in combination with Pyrosequencing analysis. AS-PCR primers for each allelic variant of the investigated SNPs were used. A mismatch introduced at the second base from the 3' end dramatically improved allele specificity. Analysis of multiple SNPs on amplified fragments using Pyrosequencing technology allowed determination of haplotypes. Genotyping of heterozygote samples after AS-PCR gave a typical monoallelic pattern at each SNP, in which the identity of the present allele depended on the allele-specific initial amplification. Haplotype determination by the described procedure proved to be highly reliable. The results obtained by Pyrosequencing technology have the benefit of being truly quantitative, enabling detection of any nonspecific allele amplification.

Animals↗

PubMed2003

Genetic variations of AA genome Oryza species measured by MITE-AFLP.

MITEs (miniature inverted-repeat transposable elements) are the major transposable elements in Oryza species. We have applied the MITE-AFLP technique to study the genetic variation and species relationship in the AA-genome Oryza species. High polymorphism was detected within and between species. The genetic variation in the cultivated species, Oryza sativa and Oryza glaberrima, was comparatively lower than in their ancestral wild species. In comparison between geographical lineages of the AA genome species, African taxa, O. glaberrima and Oryza barthii, showed lower variation than the Asian taxa, O. sativa, Oryza rufipogon, and Oryza nivara, and Australian taxon Oryza meridionalis. However, another African taxon, Oryza longistaminata, showed high genetic variation. Species relationships were analyzed by the pattern of presence or absence of homologous fragments, because nucleotide sequences of the detected MITE-AFLP fragments revealed that the same fragments in different species shared very high sequence homology. The clustering pattern of the AA-genome species matched well with the geographical origins (Asian, African and Australian), and with the Australian taxon being distant to the others. Therefore, this study demonstrated that the MITE-AFLP technique is amenable for studying the genetic variation and species relationship in rice.

Cluster Analysis↗

PubMed2005

No association between the putative functional ZDHHC8 single nucleotide polymorphism rs175174 and schizophrenia in large European samples.

BACKGROUND: It has been recently reported that a functional variant in the ZDHHC8 gene encoding a putative palmitoyltransferase directly confers susceptibility to schizophrenia in females (). METHODS: We investigated the putative risk allele (rs175174) in four schizophrenia association samples including a Bulgarian proband and parent sample (474 trios) and three case-control panels of European origin (1028 patients/1253 control subjects) in an attempt to replicate these findings. RESULTS: Our results do not support the hypothesis that genetic variation at rs175174 is associated with increased risk for schizophrenia nor do they suggest the presence of gender-specific differences. CONCLUSIONS: Our data suggest that the reported genetic association by either represents type I error resulting from sampling variance or that rs175174 is in linkage disequilibrium (LD) with the functional variant for schizophrenia and different LD patterns obscure the detection of association.

Acyltransferases↗

PubMed2002

The compositional evolution of the murid genome.

Murid rodents show much less variation in isochore base composition than do most other mammals, a difference which has been referred to as the murid shift. We have investigated the murid shift by asking (1) whether the murid shift is ongoing and (2) whether there is any evidence of selection or biased gene conversion affecting base composition in the present-day mouse genome. By estimating the ancestral base composition of protein-coding genes in murids we can confirm that the murid shift is ongoing. Tests using nongenic polymorphism data fail to reject the hypothesis that base composition is due to mutation bias alone. However, the patterns of compositional change suggested by the polymorphism and divergence data differ, suggesting the possibility of two murid shifts.

Animals↗

PubMed2006

Localization of candidate regions for a novel gene for Kartagener syndrome.

Asymmetric positioning of internal organs is a characteristics of vertebrates. The normal left-right anatomic positioning, situs solitus, sometimes does not occur normaly, leading to laterality defects. Studies in animal models have shown that laterality decisions are mediated by a cascade of genes that lead to the asymmetric expression of Nodal, LEFTA, LEFTB and PITX2 in the lateral plate mesoderm. A search for mutations in genes implicated in left-right patterning in animal models allowed genes associated with heterotaxia defects in humans to be identified. However, these genes explain only a small percentage of human situs defects, suggesting that other genes must play a role. In this study, we report a consanguineous family of Turkish origin, composed of two unaffected parents and three children, two of whom presented Kartagener syndrome. On the basis of their family history, we hypothesize autosomal recessive mode of inheritance. A genotype analysis with polymorphic markers did not show linkage with any known genes or loci causing laterality disorders. Array CGH did not detect a duplication or microdeletion greater than 1 Mb as a possible cause. Genome wide screening using 10 K Affymetrix SNP chips was performed, allowing the identification of two regions of autozygosity, one in chromosome 1 and the other on chromosome 7. In the chromosome 1 locus, a strong candidate gene, encoding the kinesin-associated protein 3 (KIF3AP) was not mutated, based on SSCP/heteroduplex analysis and direct sequencing. These data provide a basis for the identification of a novel gene implicated in Kartagener syndrome.

5' Untranslated Regions↗

PubMed2003

Trimorphic DNA variation in the receptor-like protein kinase gene in the F18L15-130 region of the wild plant Arabidopsis thaliana.

DNA variation in the F18L15-130 region, which contains a receptor-like protein kinase gene, was analyzed for the wild plants Arabidopsis thaliana and Arabis gemmifera. In A. thaliana, at least three divergent sequence types were observed (trimorphism), instead of two distinct sequence types (dimorphism) detected in most of other nuclear gene regions studied for this plant species. Intragenic recombinations among the divergent sequence types generated four recombinant sequence types, although pattern of intragenic recombinations was complex. The estimated nucleotide variation in A. thaliana was the highest (pi = 0.0226 and theta = 0.0228) among genes investigated in this plant so far. The high level of nucleotide variation is due to divergence among the three distinct sequence types, each of which has a low level of nucleotide variation. Tests of Tajima, and Fu and Li did not detected deviation from neutrality, except for replacement sites, for which significantly negative Fu and Li's test value was detected. These results suggest that the receptor-like protein kinase gene in this region is functional. Possible causes for the trimorphic pattern of DNA polymorphism was discussed.

Arabidopsis↗

PubMedDate not supplied

Detection of a novel alteration of the Axin gene in various pediatric neoplasms.

The Wnt signaling pathway is conserved in various species from worms to mammals, and plays critical roles in development, cellular proliferation and differentiation. As part of Wnt signal transduction, the function of the Axin complex is inhibited, leading to the accumulation of beta-catenin protein. Axin gene mutations have been detected in several kinds of human cancers. In this study, we investigated Axin gene alterations in a series of 58 pediatric neoplasms including neuroblastomas, teratomas, rhabdomyosarcomas. Forty-eight non-tumor tissues were used as a control series to compare gene alterations and their frequencies between tumors and normal tissues. The whole coding region of the Axin gene was examined by PCR-SSCP method using 24 sets of the primers. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. In total, we identified six variants in the exons and four intronic nucleotide substitutions in the tumor series. Similar sequence variants except a rare sequence variant at codon 98 (CCG right curved arrow CTG) were observed in the control series and these were regarded as non-pathogenetic polymorphisms. Our results indicated that a tumor-associated mutation of the Axin gene is generally a rare event in our series of pediatric neoplasms.

Axin Protein↗

PubMed1996

Mutational analysis of RAG-1 in lymphoid malignancies.

Illegitimate recombinase activity promoted by the recombination activating RAG-1 and RAG-2 is assumed to be involved in the pathogenesis of the chromosomal translocations observed in lymphoid neoplasias. We analyzed the complete coding region of the RAG-1 gene in patients with lymphoid neoplasis using a multiple PCR-SSCP (single strand conformation polymorphism) strategy. Nine multiple myelomas, 17 non-Hodgkin's lymphomas, 18 acute lymphocytic leukemias, 37 chronic lymphocytic leukemias and 33 non-neoplastic controls were studied. To screen the entire RAG-1 gene we used primers overlapping genomic segments of the RAG-1 coding sequence (nucleotides 87 to 3311). Samples with an abnormal band pattern in the SSCP were cloned and sequenced. Successful amplification was achieved with our protocol. The multiple PCR-SSCP analysis proved to be a feasible and sensitive strategy for studying variations in the sequence of the RAG-1 gene. No mutations other than the three previously reported sequence variations were detected. Although mutations in this gene do not appear to be common in lymphoid neoplasias, it would be interesting to ascertain whether the different variant forms of RAG-1 protein have an abnormal recombinase activity.

DNA Mutational Analysis↗

PubMed2005

Phosphorylation states of cell cycle and DNA repair proteins can be altered by the nsSNPs.

BACKGROUND: Phosphorylation is a reversible post-translational modification that affects the intrinsic properties of proteins, such as structure and function. Non-synonymous single nucleotide polymorphisms (nsSNPs) result in the substitution of the encoded amino acids and thus are likely to alter the phosphorylation motifs in the proteins. METHODS: In this study, we used the web-based NetPhos tool to predict candidate nsSNPs that either introduce or remove putative phosphorylation sites in proteins that act in DNA repair and cell cycle pathways. RESULTS: Our results demonstrated that a total of 15 nsSNPs (16.9%) were likely to alter the putative phosphorylation patterns of 14 proteins. Three of these SNPs (CDKN1A-S31R, OGG1-S326C, and XRCC3-T241M) have already found to be associated with altered cancer risk. We believe that this set of nsSNPs constitutes an excellent resource for further molecular and genetic analyses. CONCLUSION: The novel systematic approach used in this study will accelerate the understanding of how naturally occurring human SNPs may alter protein function through the modification of phosphorylation mechanisms and contribute to disease susceptibility.

Alleles↗

PubMed2006

Analysis of single nucleotide polymorphism sites in exon 4 of the p53 gene using high-performance liquid chromatography electrospray ionization mass spectrometry tandem mass spectrometry.

Three groups of four oligonucleotides with special single nucleotide polymorphisms (SNP) sites in exon 4 of the p53 gene were analyzed with ion-pair reversed-phase high-performance liquid chromatography electrospray ionization mass spectrometry tandem mass spectrometry. The retention order of four oligonucleotides with SNPs was C < G < A < T, regardless of whether the polymorphisms were at the 3' end, the 5' end, or the middle of the oligonucleotides. The charge state of the molecular ion affects the MS/MS spectra of the oligonucleotides. SNPs at the 3' end can be easily identified from the fragmentation pattern of the 2- charge state, but not from the 3- charge state, especially from the w1 fragment. The single base may be taken as the symbol of the 5' end SNP site derived from [M3H]2, but not from the [M3H]2 charge state. The oligonucleotides with SNPs in the middle were also determined from the [M2H]2 precursor ion.

Chromatography, High Pressure Liquid↗