Biomedical subjects

Takashi Kitano

Publications and source records attributed to Takashi Kitano.

10 recordsLinked to original sources

PubMed2006

Origin and evolution of gene for prolactin-induced protein.

Prolactin-induced protein (PIP) is a small protein secreted into the fluid in several glands. We determined the PIP coding sequences of 5 hominoid species and estimated the numbers of synonymous and nonsynonymous substitutions for each branch of the mammalian PIP gene tree. The branch connecting hominoids and Old World monkeys showed significantly higher nonsynonymous than synonymous substitutions. These changes tended to be accumulated in the fibronectin-binding domain. Many other primate branches also showed higher nonsynonymous than synonymous substitutions, thus suggesting that the PIP genes of primates have experienced some kind of positive selection. We also considered the phylogenetic relationship of the PIP gene with the alpha-2-macroglobulin gene family. The results indicate that the PIP gene arose by partial gene duplication from a member of the alpha-2-macroglobulin gene family after the divergence between amphibians and other tetrapods.

Amino Acid Sequence↗

PubMed2006

Two universal primer sets for species identification among vertebrates.

The aim of this study was to develop a simple method using universal primers for species identification based on direct PCR sequencing. Two primer sets were designed based on the conserved regions of the 12S and 16S rRNA loci detected by the comprehensive sequence comparison among 30 mammalian whole mitochondrial genomes. In humans, the expected sizes of PCR products of the 12S and 16S rRNAs were 215 and 244 bp, respectively. Both primer sets successfully amplified the expected PCR products from various kinds of vertebrates including mammals, birds, reptiles, amphibians, and fish, and the sequenced segments contained sufficient nucleotide differences to identify each animal species. A case example of the identification of a piece of buried bone of unknown species is presented, and the species was identified as a pig by this method.

Animals↗

PubMed2006

Conservation of a platelet activating domain of Aggrus/podoplanin as a platelet aggregation-inducing factor.

Human Aggrus/podoplanin is an identified platelet aggregation-inducing factor of cancer cells, which is also known as a specific marker of lymphatic endothelium. Human Aggrus was known to be expressed in seminoma, squamous cell carcinoma, malignant mesothelioma, sarcomas and several brain tumors. In our previous studies, the sialylated O-glycan of human and mouse Aggrus were shown to be critical for its platelet aggregation-inducing activity in the experiments using the glycosylation-deficient Chinese hamster ovary (CHO) cell lines. We newly cloned Aggrus homologues from rat, hamster, dog and bovine cDNAs, in addition to the human and mouse cDNAs, and confirmed there are three tandem repeats of the platelet aggregation-stimulating (PLAG) domain in Aggrus, which were conserved in all homologues. We found that bovine Aggrus has a sporadic deletion mutation in the first PLAG domain, and lacks platelet aggregation-inducing activity. We introduced point mutation in the PLAG domain of Aggrus and showed that either the first or last PLAG domain is critical for activity, but not the middle domain. In addition, we studied the molecular evolutionary process of the PLAG domain of Aggrus. The PLAG domain and its activity appeared after the divergence of avians and mammals. In conclusion, we provide evidence that Aggrus homologues conserved the segment of EDxxVTPG in their extracellular domain which are critical for their platelet aggregation-inducing activities.

Amino Acid Sequence↗

PubMed2005

Evolutionary conservation of 5' upstream sequence of nine genes between human and great apes.

Nucleotide sequences of nine 5' upstream gene regions for human, chimpanzee, gorilla, and orangutan were determined. We estimated nucleotide differences (d) for each region between human and great apes. The overall d was 0.027 (ranged from 0.004 to 0.052). Rates of nucleotide substitution were estimated by using d and divergence times of human, chimpanzee, gorilla, and orangutan. The overall rate of nucleotide substitution between human and other hominoids was estimated to be 0.52-0.85 x 10(-9). This rate in 5' upstream regions was lower than that of synonymous sites, suggesting that 5' upstream regions have evolved under some functional constraints. Because lower rates have been reported for coding sequences in primates compared to rodents, we also estimated the rate (1.17-1.76 x 10(-9)) of nucleotide substitutions for the corresponding 5' upstream regions in rodents (mouse/rat comparison). Thus the primate rate was lower than rodent rate also for the 5' upstream regions.

5' Flanking Region↗

PubMed2004

Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia.

Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia--and, more recently, for bipolar disorder--on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P=.0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.

Black or African American↗

PubMed2004

Human-specific amino acid changes found in 103 protein-coding genes.

We humans have many characteristics that are different from those of the great apes. These human-specific characters must have arisen through mutations accumulated in the genome of our direct ancestor after the divergence of the last common ancestor with chimpanzee. Gene trees of human and great apes are necessary for extracting these human-specific genetic changes. We conducted a systematic analysis of 103 protein-coding genes for human, chimpanzee, gorilla, and orangutan. Nucleotide sequences for 18 genes were newly determined for this study, and those for the remaining genes were retrieved from the DDBJ/EMBL/GenBank database. The total number of amino acid changes in the human lineage was 147 for 26,199 codons (0.56%). The total number of amino acid changes in the human genome was, thus, estimated to be about 80,000. We applied the acceleration index test and Fisher's synonymous/nonsynonymous exact test for each gene tree to detect any human-specific enhancement of amino acid changes compared with ape branches. Six and two genes were shown to have significantly higher nonsynonymous changes at the human lineage from the acceleration index and exact tests, respectively. We also compared the distribution of the differences of the nonsynonymous substitutions on the human lineage and those on the great ape lineage. Two genes were more conserved in the ape lineage, whereas one gene was more conserved in the human lineage. These results suggest that a small proportion of protein-coding genes started to evolve differently in the human lineage after it diverged from the ape lineage.

Animals↗

PubMed2003

Gene diversity patterns at 10 X-chromosomal loci in humans and chimpanzees.

We have investigated the pattern and extent of nucleotide diversity in 10 X-chromosomal genes where mutations are known to cause mental retardation in humans. For each gene, we sequenced the entire coding region from cDNA in humans, chimpanzees, and orangutans, as well as about 3 kb of genomic DNA in 20 humans sampled worldwide and in 10 chimpanzees representing two "subspecies." Overall nucleotide diversity in these genes is about twofold lower in humans than in chimpanzees, and nucleotide diversity within and between species is low, suggesting that a high level of functional constraint acts on these genes. Strikingly, we find that a summary of the allele frequency spectrum is significantly correlated in humans and chimpanzees, perhaps reflecting very similar levels of constraint at these genes in the two species. A possible exception is FMR2, which shows a higher number of nonsynonymous than synonymous substitutions on the human lineage, suggesting the action of positive selection.

Animals↗

PubMed2003

Evolution of the cystatin B gene: implications for the origin of its variable dodecamer tandem repeat in humans.

The human cystatin B gene contains a variable number of 12-bp tandem repeats in its promoter region, of which the common alleles contain two or three copies and unusual expansion causes progressive myoclonus epilepsy of the Unverricht-Lundborg type. We undertook a comprehensive analysis of the genomic sequence to address the evolutionary events of this variable repeat. By examination of a contiguous genome sequence spanning 5.0 kb and linkage analysis of detected polymorphic changes, we identified six major intragenic haplotypes in unrelated Japanese subjects. The number of normal repeats was closely correlated with these alleles, indicating that changes in the array should be comparatively rare events during human evolution. To examine the origin of the repeat array further, we also analyzed five primate genomes. Repetitive polymorphism was unlikely in hominoids, and the array originated with the dodecamer itself in the course of primate evolution. The variability conceivably developed after the separation to humans.

Cystatin B↗

PubMed2002

Molecular evolution of FOXP2, a gene involved in speech and language.

Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution.

Alleles↗

PubMed2002

Extreme mtDNA homogeneity in continental Asian populations.

Mitochondrial DNA (mtDNA) variation in continental Asia has not been well-studied. Here, we report mtDNA HV1 sequences for 84 Xi'an and 82 Changsha Han Chinese, 89 Honshu Japanese, and 35 Vietnamese. Comparison of these sequences with other Asian mtDNA sequences reveals high variability within populations, but extremely low differentiation among Asian populations. Correlations between genetic distance and geographic distance, based on mtDNA and Y chromosome variation, indicate a higher migration rate in females than in males. This may reflect patrilocality, as suggested previously, but another plausible hypothesis is that the demographic expansion associated with the spread of agriculture in Asia may be responsible for the extreme genetic homogeneity in Asia.

Asia↗