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PubMed2004

The SPANX gene family of cancer/testis-specific antigens: rapid evolution and amplification in African great apes and hominids.

Human sperm protein associated with the nucleus on the X chromosome (SPANX) genes comprise a gene family with five known members (SPANX-A1, -A2, -B, -C, and -D), encoding cancer/testis-specific antigens that are potential targets for cancer immunotherapy. These highly similar paralogous genes cluster on the X chromosome at Xq27. We isolated and sequenced primate genomic clones homologous to human SPANX. Analysis of these clones and search of the human genome sequence revealed an uncharacterized group of genes, SPANX-N, which are present in all primates as well as in mouse and rat. In humans, four SPANX-N genes comprise a series of tandem duplicates at Xq27; a fifth member of this subfamily is located at Xp11. Similarly to SPANX-A/D, human SPANX-N genes are expressed in normal testis and some melanoma cell lines; testis-specific expression of SPANX is also conserved in mouse. Analysis of the taxonomic distribution of the long and short forms of the intron indicates that SPANX-N is the ancestral form, from which the SPANX-A/D subfamily evolved in the common ancestor of the hominoid lineage. Strikingly, the coding sequences of the SPANX genes evolved much faster than the intron and the 5' untranslated region. There is a strong correlation between the rates of evolution of synonymous and nonsynonymous codon positions, both of which are accelerated 2-fold or more compared to the noncoding sequences. Thus, evolution of the SPANX family appears to have involved positive selection that affected not only the protein sequence but also the synonymous sites in the coding sequence.

Amino Acid Sequence↗
PubMed2002

Mutational analysis of CD28 in coeliac disease.

BACKGROUND: Coeliac disease shows a strong genetic predisposition involving HLA-DQ2 and non-HLA components. The CD28 cell surface molecule, encoded by CD28, represents a potential candidate coeliac disease susceptibility gene. Furthermore, some studies have demonstrated linkage to the CD28/CTLA4 gene region. To investigate whether germline mutations in CD28 contribute to coeliac disease susceptibility, we have carried out a comprehensive analysis of the gene in Swedish patients with biopsy-proven disease. METHODS: Blood samples were collected from 52 children with biopsy proven coeliac disease attending one Swedish centre. DNA was extracted from lymphocytes and all exons and intron-exon boundaries of CD28 were screened for mutations. Analysis of CD28 was undertaken by a combination of conformation specific gel electrophoresis and direct sequencing. RESULTS: Three sequence variants were identified: a synonymous G-->4A substitution at position 3 of codon 35 encoding alanine, a synonymous G-->A substitution at position 3 of codon 70 encoding glycine, and a T-->C substitution at nucleotide +17 of intron 3. No pathogenic variants were detected. CONCLUSIONS: There is no evidence from this study that mutations in CD28, which lead to an altered protein, contribute to coeliac disease susceptibility.

Adolescent↗
PubMed2001

HIV type 1 genetic diversity is a major obstacle for antiretroviral drug resistance hybridization-based assays.

Human immunodeficiency virus type 1 (HIV-1) is characterized by high genetic diversity. Current antiretroviral (ARV) drug resistance genotyping assays have been designed on the basis of the most prevalent sequence patterns circulating in the United States and Europe, which belong to the B subtype. However, little is known about their performance on non-B subtype samples. In Argentina, circulating forms have been characterized as subtypes B, C, F, and B/F recombinant forms. Our aim was to analyze the association between the genetic diversity of HIV-1 forms circulating in Argentina and the lack of reactivity at codon 74 in an ARV drug resistance hybridization-based assay. Samples taken from 93 HIV-1-infected individuals of Buenos Aires, Argentina were studied. The reverse transcriptase (RT) region of HIV-1 was genotypically assessed by a line probe assay (INNO-LiPA HIV-1 RT; Innogenetics, Ghent, Belgium) and automatic sequencing (TruGene and OpenGene; Visible Genetics, Toronto, Canada). Phylogenetic and intersubtype recombination analyses were carried out, showing that 52 of 93 (55.9%) samples belonged to subtype B, whereas 41 of 93 (44.1%) showed a (5') F1/B (3') subtype recombinant genomic structure. For codon 74 in the LiPA test, 4 of 52 (7.7%) B-subtype samples were nonreactive, whereas 27 of 41 (65.9 %) F1/B recombinant samples showed a nonreacting result, indicating a significant difference in the subtype distribution of the nonreacting samples. The presence of a synonymous polymorphism at codon 72 of RT (AGA --> AGG) associated with the lack of reaction at codon 74 in LiPA, was more prevalent in F1/B subtype recombinant samples (p < 0.001). The present data indicate that HIV-1 genetic diversity is a major obstacle for ARV drug resistance hybridization-based assays.

Base Sequence↗
PubMed2006

Variation in evolutionary processes at different codon positions.

Evolutionary studies commonly model single nucleotide substitutions and assume that they occur as independent draws from a unique probability distribution across the sequence studied. This assumption is violated for protein-coding sequences, and we consider modeling approaches where codon positions (CPs) are treated as separate categories of sites because within each category the assumption is more reasonable. Such "codon-position" models have been shown to explain the evolution of codon data better than homogenous models in previous studies. This paper examines the ways in which codon-position models outperform homogeneous models and characterizes the differences in estimates of model parameters across CPs. Using the PANDIT database of multiple species DNA sequence alignments, we quantify the differences in the evolutionary processes at the 3 CPs in a systematic and comprehensive manner, characterizing previously undescribed features of protein evolution. We relate our findings to the functional constraints imposed by the genetic code, protein function, and the types of mutation that cause synonymous and nonsynonymous codon changes. The results increase our understanding of selective constraints and could be incorporated into phylogenetic analyses or gene-finding techniques in the future. The methods used are extended to an overlapping reading frame data set, and we discover that overlapping reading frames do not necessarily cause more stringent evolutionary constraints.

Base Sequence↗
PubMed2002

Silent mutations affect in vivo protein folding in Escherichia coli.

As an approach to investigate the molecular mechanism of in vivo protein folding and the role of translation kinetics on specific folding pathways, we made codon substitutions in the EgFABP1 (Echinococcus granulosus fatty acid binding protein1) gene that replaced five minor codons with their synonymous major ones. The altered region corresponds to a turn between two short alpha helices. One of the silent mutations of EgFABP1 markedly decreased the solubility of the protein when expressed in Escherichia coli. Expression of this protein also caused strong activation of a reporter gene designed to detect misfolded proteins, suggesting that the turn region seems to have special translation kinetic requirements that ensure proper folding of the protein. Our results highlight the importance of codon usage in the in vivo protein folding.

Amino Acid Substitution↗
PubMed2005

Heterozygous mutations of growth hormone receptor gene in children with idiopathic short stature.

OBJECTIVE: The term idiopathic short stature (ISS) describes children: (a) whose height is more than two standard deviations below the mean; (b) with normal or slow height velocity; (c) of normal birth weight; (d) showing an absence of specific endocrine abnormalities; and (e) having no evidence of chronic physical or psychological illness. It has been suggested that partial growth hormone (GH) insensitivity due to heterozygous mutations of the GH Receptor gene may account for some cases of ISS. DESIGN AND METHODS: GHR gene was investigated (SSCP assay and direct sequencing) in 37 ISS patients. Fifty controls were recruited from the same geographic area as the patients; age and gender were stratified to match controls to patients. RESULTS: We observed the previously described transition A>G (GGA>GGG) of position 3 of codon 168, determining the synonymous change G168G in 22 of 37 patients (12 homozygous and 10 heterozygous) and in 23 of 50 controls (16 homozygous and 7 heterozygous). The relative allele frequency was similar in patients and in controls. In one ISS patient we identified a novel transition T>C (TGT>TGC) of position 3 of codon 94 , determining the synonymous change C94C. In another patient we demonstrated a novel heterozygous transition T>C (GTC>GCC) of the position 2 of codon 144, determining the missense mutation V144A, These mutations were not found in 100 control chromosomes. CONCLUSIONS: Heterozygous mutations of the GHR gene are uncommon in Italian ISS patients, who are selected for adequate GH levels. However the observed incidence of 2 mutations out of 37 ISS patients (i.e., 5%) is not different from the one previously reported in the literature.

Adolescent↗
PubMed2006

Identification of rare mutations of synaptogyrin 1 gene in patients with schizophrenia.

Synaptogyrin 1 gene (SYNGR1) is considered as a positional candidate gene for schizophrenia because of its location at chromosome 22q13, a region linked to schizophrenia, and its reduced expression in postmortem brain of patients with schizophrenia. Additionally, genetic studies also reported association of SYNGR1 is with schizophrenia and bipolar disorder in southern India. Prompted by these findings, we were interested to know if SYNGR1 is also associated with schizophrenia in our population. Therefore, we systematically searched for SYNGR1 mutations in a cohort of Han Chinese patients from Taiwan. Four single nucleotide polymorphisms (SNPs) were identified, including three at the putative core promoter region (g.-673A>C, g.-377G>A and g.-318G>T) that are in strong linkage disequilibrium and one in intron 2 (IVS2-64C>G). Computer program predicts that g.-637A>C and g.318G>T may change transcription binding sites of AP-1 and TGT3, respectively. We further carried out SNP- and haplotype-based case-control association studies of these tress SNPs with schizophrenia. However, no association was detected between these SNPs and schizophrenia in our sample. Nevertheless, we identified several rare mutations in exon 6 of SYNGR1 gene in our patient cohort (n=497), including a 3-bp (AAC) in-frame insertion between codon 202 and 203 (P202_T203insN) in two patients, an A-to-G missense mutation (c.665A>G) at codon 222 (D222G) in one patient, a synonymous mutation (c.669C>T) at codon 223 (T223T) in one patient, and a C-to-T at 3' UTR of SYNGR1 (c.772C>T) in one patient. These are mutations were not found in 507 control subjects, suggesting further functional assays are warranted to verify their relevance to the pathogenesis of schizophrenia.

Adult↗
PubMed2006

[Melanin traits of Yunnan black bone sheep and TYR gene polymorphism].

The "black bone and muscle" is cardinal melanin trait of black bone sheep. The black bone sheep and the native sheep in Lanping and Luomuni sheep were chosen as materials for the measurement of TYR activity of blood and melanin content of tissues and organs. Moreover, we compared characteristic structure of melanin of black bone sheep with silky fowls. The results showed as follows: TYR activity was significantly different between black and non-black bone sheep (P<0.05); the total character of infrared spectrum (IR) of melanin of black bone sheep resembled silky fowls; and melanin was eumelanin. We firstly cloned exon1 667bp sequence of TYR gene and determined TYR gene polymorphism of black and non-black bone sheep by PCR-RFLP. Compared with sequence of TYR gene of non-black bone sheep, there were two nucleotide mutation sites in exon1 of black bone sheep, located in No.64 and No.154 amino acid codons, respectively; but they were synonymics mutation. We designed restriction site in codon 64 and check up TYR gene polymorphism. The result showed the mutation site together with the close linked gene influenced melanin trait deposition. It suggests there should be functional mutation related with melanin trait. Furthermore, there was significant correlation between TYR gene polymorphism and coat color of sheep (P<0.01), indicating TYR could influence synthesis of coat color of sheep.

Animals↗
PubMed1993

Evolutionary origin and radiation of the avian-adapted non-motile salmonellae.

Multilocus enzyme electrophoresis was employed to estimate chromosomal genotypic diversity and relationships among 131 isolates of the non-motile Salmonella biotypes Gallinarum and Pullorum (serotype 1, 9, 12:-:-) that cause fowl typhoid and pullorum disease, respectively. Thirteen electrophoretic types (ETs), marking clones, were distinguished, and construction of a neighbour-joining phylogenetic tree revealed three lineages: one consisted of five ETs of Gallinarum, a second included seven ETs of Pullorum, and a third was represented by a single ET (Ga/Pu 1) that is intermediate between those of the other two lineages in both multilocus enzyme genotype and biochemical properties. Enzyme genotype analysis and comparative nucleotide sequencing of the phase 1 flagellin gene (fliC), the hook-associated protein 1 gene (flgK), and the 6-phosphogluconate dehydrogenase gene (gnd) identified serotype Enteritidis (1, 9, 12:g, m:-) as a close relative of the non-motile salmonellae. In most strains of biotype Gallinarum, the fliC gene is complete, intact and identical in sequence to that of Enteritidis, but isolates of three ETs had a stop codon at position 495. The fliC sequences of the ETs of Pullorum differed from that of Enteritidis in having non-synonymous changes in either two or three codons and a synonymous change in one codon. The sharing of distinctive alleles at three metabolic enzyme loci and a stop codon in flgK indicates that the non-motile salmonellae are monophyletic and that their most recent common ancestor was non-motile. Since diverging from that ancestor, the Pullorum lineage has evolved more rapidly than the Gallinarum and Ga/Pu 1 lineages.

Animals↗
PubMed1995

Mitochondrial-DNA sequence evidence on the phylogeny of Australian jack-jumper ants of the Myrmecia pilosula complex.

Australian ants of the Myrmecia pilosula species complex include some individuals (in M. croslandi) with the lowest possible metazoan chromosome number of 2n = 2. Others in this cluster of sibling species have much higher numbers, the known maximum being 2n = 32. Two species (M. pilosula and M. 'banksi') are believed on cytogenetic and morphological grounds to have hybridized over a long period. To investigate the phylogeny and age of this group relative to the congeneric outgroup species M. gulosa, we sequenced part of the cytochrome b gene and the intergenic sequence between it and a primer anchored on the nearby tRNA(UCNSer) gene and analyzed the coding region using bootstrapped parsimony and neighbor-joining trees using the numbers of synonymous and nonsynonymous codons per site. The intergenic space demonstrated a profusion of repeated sequences, and only very closely related sequences (as judged by that for cytochrome b) showed detectable similarity at this almost 100% A+T region. In agreement with predictions from karyotype studies, the phylogenetic analyses showed that M. croslandi is the sister group to the other siblings; the time of separation of M. croslandi from the rest of the pilosula group is unexpectedly ancient. Other relationships were poorly resolved, but the results suggest that M. 'banski' and M. pilosula cluster together, as expected on cytogenetic grounds, and the tentative suggestion of close affinity of the M. pilosula samples and two "PB" samples supports derivation of PB from female M. pilosula and male M. 'banksi.'

Animals↗
PubMed1993

Phylogenetic relationships of ferns deduced from rbcL gene sequence.

Part of the large subunit of the ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) gene (rbcL) was sequenced from three fern species: Adiantum capillus-veneris, Botrypus strictus, and Osmunda cinnamomea var. fokiensis. This region included 1,333 base pairs, about 90% of the gene. Maximum likelihood analysis of the deduced amino acid sequences indicated that (1) Botrypus (Ophioglossaceae) clustered monophyletically with other ferns (Adiantum, Angiopteris, Osmunda); the closest relative to Botrypus among the three species was Osmunda, which did not support the hypothesis that the Ophioglossaceae are linked to the progymnosperm-seed plant lineage. (2) Eusporangiate ferns containing Botrypus (Ophioglossaceae) and Angiopteris (Marattiaceae) were a paraphyletic group. (3) Seed plants and the four fern species examined formed a monophyletic group, but ferns and bryophytes (liverwort) did not. Variations in rates of substitution for synonymous and nonsynonymous codons were found in fern lineages.

Amino Acid Sequence↗
PubMed1978

Neutral changes during divergent evolution of hemoglobins.

A comparison of the mRNAs for rabbit and human beta-hemoglobins shows that synonymous changes in codons have accumulated three times as rapidly as nucleotide replacements that produced changes in amino acids. This agrees with predictions based on the so-called 'neutral theory'. In addition, seven codon changes that appear to be single-base changes (according to 'maximum parsimony') are actually two-base changes. This indicates that the construction of "primordial sequences" is of limited signficance when based on inferences that assume minimum base changes for amino acid replacements.

Amino Acids↗
PubMed2006

Identification of two novel HLA-C alleles, Cw*070105 and Cw*1408, from East African women.

HLA-C was shown to be a highly polymorphic gene that can be accurately typed by sequencing methodologies. We report two novel HLA-C alleles identified during sequence-based typing of East African populations; the novel alleles were confirmed by sequencing two separate polymerase chain reaction products and by molecular cloning and sequencing multiple clones. The first new allele is identical to Cw*0701 except for a single-nucleotide synonymous substitution at codon 182 (GCA-->GCG). The new allele has been named by the WHO nomenclature committee as Cw*070105. The second new allele is identical to Cw*1403 except for a nonsynonomous change at codon 21 (CAC-->CGC), changed from histidine to arginine. The new allele has been named by the WHO nomenclature committee as Cw*1408.

Alleles↗
PubMed2001

Evidence for purifying selection acting on silent sites in BRCA1.

In mammals, it is usually assumed that selection cannot be strong enough to act on nucleotide mutations that do not cause a change at the protein level (i.e. 'silent' or 'synonymous' mutations). Here we report the results of a molecular evolutionary analysis of BRCA1. We find a repeatable pronounced peak in the ratio of nonsynonymous to synonymous substitutions between codons 200-300. Unusually, this peak is caused by a plummet in the silent-site rate of evolution. The most parsimonious interpretation of these data is that purifying selection is acting on silent sites.

Animals↗
PubMed1997

Description of a new HLA-E (E*01031) allele and its frequency in the Spanish population.

An HLA-E polymorphism study by oligotyping and DNA sequencing was carried out in the Spanish population. As a result, a new HLA-E allele (E*01031) initially assigned by polymerase chain reaction oligotyping as E*0104 was found. This allele presents a synonymous change at codon 77 (AAT-->AAC; Asn) when compared with the E*01032 allele. This position is located in the alpha-helix (alpha 1-domain) and is involved in the peptide binding region of the hypothetical HLA-E molecule. Among 60 Spanish individuals, HLA-E*0101 presents the highest phenotype frequency, followed in decreasing order by E*01032, E*01031 (new allele), and E*0102. Also, new partial intron 1 and complete intron 2 sequences from E*0101, E*01031, and E*01032 are described; the sequences are identical among the three forms. However, the intron 2 sequence of the E*0102 allele bears a two-base deletion not found in apes.

Alleles↗
PubMed2001

A novel HLA-DRB1 sequence, DRB1*11272.

We describe the complete exon 2 sequence of a novel HLA-DRB1 allele, DRB1*11272. This allele differs from the DRB1*11271 allele by a synonymous mutation in codon 77 where an AAT is replaced with AAC, both encode for the amino acid asparagine. The same motif at codon 77 has also been found in DRB1*1107, DRB1*1333, DRB1*0422 and in most DRB1*03 alleles. A partial exon 2 sequence of this allele has previously been deposited in the EMBL Sequence Database under the accession number AF186407.

Alleles↗
PubMed2005

Interethnic variability of ERCC2 polymorphisms.

Excision Repair Cross-Complementing Rodent Repair Group 2 (ERCC2) plays an important role in DNA repair by eliminating bulky DNA adducts produced by platinum agents during the nucleotide excision repair pathway. Several studies have associated polymorphisms in ERCC2 with response to platinum therapy, lung cancer risk, and DNA repair capacity. This study examined ERCC2 polymorphisms and haplotype structure across 18.9 kb in 95 European, 95 African, and 95 Asian individuals. Single-nucleotide polymorphisms (SNPs) (ERCC2 -9164 A>T, -1989 A>G, -516 G>A, 468 C>A [Arg156Arg], 1737 C>T [Val579Val], 2133 C>T [Asp711Asp], and 2251 T>G [Lys751Gln]) were mined and mapped using Golden Path, PolyMAPr, and Promolign. Genotyping was performed using PCR and pyrosequencing. Allele frequencies ranged from 0 to 0.47 (Europeans), 0.05 to 0.72 (Africans), and 0 to 0.47 (Asians). The synonymous cSNP at codon 579 could not be confirmed in our populations. There were significant differences in haplotype structure and frequency between populations. This information on ERCC2 genomic structure will allow the construction of definitive studies to clarify the clinical role of this important gene.

Adult↗
PubMed2000

Analysis of the peroxisome proliferator activated receptor gamma (PPARgamma) gene in HAIRAN syndrome with obesity.

OBJECTIVES: To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor gamma (PPARgamma), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARgamma and the degree of insulin resistance. DESIGN: A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype. PATIENTS: Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non-diabetic non-obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non-diabetic non-obese individuals. MEASUREMENTS: Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARgamma isoforms (PPARgamma1 and PPARgamma2) for single-stranded conformational polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique. RESULTS: A synonymous substitution in codon 477 (CACHis --> CATHis) was found in one patient. A missense mutation in codon 12 of PPARgamma2 (CCAPro --> GCAAla) was found in another patient, but not in any of 25 non-diabetic, non-obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied. CONCLUSIONS: Mutations in the PPARgamma gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.

Acanthosis Nigricans↗