Genetic polymorphism of alpha-1-antitrypsin in macaque species

Thirty-two phenotypes of alpha-1-antitrypsin (al-AT) controlled by 18 codominant alleles of PI_mac locus were identified by isoelectric focusing in 1.121 macaques of nine species. In terms of al-AT polymorphism macaque species vary markedly from nearly monomorphic (Macaca mulatta, M. arctoides) to highly polymorphic (M. nemestrina, M. fascicularis). Only 4 of 18 PI_mac alleles are common for two or more macaque species, the rest of the alleles are species-specific.     

Identification of the nucleotide substitution that generates the fourth polymorphic site in human deoxyribonuclease I (DNase I)

In addition to the three polymorphic sites responsible for protein polymorphism, a new polymorphic site has been identified in intron 7 of the human deoxyribonuclease I (DNase I) gene. Three phenotypes were observed on single-strand conformational polymorphism analysis of a 266-bp polymerase chain reaction-amplified fragment containing exon 7 and part of intron 7 of the human DNase I gene. DNA sequencing analysis demonstrated that a C-G substitution occurred at position 1978 in intron 7. This substitution was confirmed by restriction fragment length polymorphism analysis, since a new Msp1 site is created by the substitution. Population and family studies showed that the inheritance of the genotypes for DNase I C1978G polymorphism is controlled by two codominant alleles, tentatively designated DNASE1*1978C and *1978G. The gene frequencies in a Japanese population were significantly different from those in a Caucasian (German) population. The C1978G polymorphism is in linkage disequilibrium with the common DNase I protein phenotypes 1, 1–2, and 2. Received: 20 March 1996 / Revised: 14 May 1996     

Association analysis of the common varieties of IL17A and IL17F genes with the risk of knee osteoarthritis

Osteoarthritis is mediated by various types of cytokines, growth factors, and inflammatory factors that the role of the interleukin-17 family in this disease is becoming increasingly apparent. The aim of this study is to determine the association between the common polymorphisms of IL17A (including rs2275913) and IL17F (including rs2397084 and rs763780) genes with the knee osteoarthritis risk which was followed by a bioinformatics approach. In a case-control study, 254 participants consisting of 127 healthy individuals and 127 subjects with knee osteoarthritis referring to Shahid Beheshti Hospital dependents on Kashan University of Medical Sciences (Kashan, Iran) were enrolled. After samples collection, the polymorphisms genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Finally, some bioinformatics tools were used to analyze the molecular effects of the three studied polymorphisms. Data analysis showed a significant association between rs2275913-GA genotype and the decreased risk of knee osteoarthritis (OR = 0.57, 95% CI = 0.33-0.97, P = .040). However, rs763780-AG genotype (OR = 2.29, 95%CI = 1.11-4.69, P = .024) and rs763780-G allele (OR = 2.01, 95% CI = 1.09-3.72, P = .026) were associated with an increased risk of knee osteoarthritis. However, no significant associations were found between the rs2397084 polymorphism and knee osteoarthritis risk. Our structural analysis revealed that the rs2275913 polymorphism could create a new binding site for TFII-I at the promoter region of IL17A. Also, rs2397084 and rs763780 could significantly affect the function and structure of IL17A. Based on our findings, rs2275913 and rs763780 could be considered as protective and risk factors for knee osteoarthritis, respectively. Therefore, these polymorphisms can be considered as biomarkers for the screening of knee osteoarthritis susceptible persons.     

The apolipoprotein (a) gene: a transcribed hypervariable locus controlling plasma lipoprotein (a) concentration

Lipoprotein(a) [Lp(a)] is a quantitative trait in human plasma. Lp(a) consists of a low-density lipoprotein and the plasminogen-related apolipoprotein(a) [apo(a)]. The apo(a) gene determines a size polymorphism of the protein, which is related to Lp(a) levels in plasma. In an attempt to gain a deeper insight into the genetic architecture of this risk factor for coronary heart disease, we have investigated the basis of the apo(a) size polymorphism by pulsed field gel electrophoresis of genomic DNA employing various restriction enzymes (SwaI, KpnI, KspI, SfiI, NotI) and an apo(a) kringle-IV-specific probe. All enzymes detected the same size polymorphism in the kringle IV repeat domain of apo(a). With KpnI, 26 different alleles were identified among 156 unrelated subjects; these alleles ranged in size from 32kb to 189kb and differed by increments of 5.6kb, corresponding to one kringle IV unit. There was a perfect match between the size of the apo(a) DNA phenotypes and the size of apo(a) isoforms in plasma. The apo(a) DNA polymorphism was further used to estimate the magnitude of the apo(a) gene effect on Lp(a) levels by a sib-pair comparison approach based on 253 sib-pairs from 64 families. Intra-class correlation of log-transformed Lp(a) levels was high in sib-pairs sharing both parental alleles (r = 0.91), significant in those with one common allele (r = 0.31), and absent in those with no parental allele in common (r = 0.12). The data show that the intra-individual variability in Lp(a) levels is almost entirely explained by variation at the apo(a) locus but that only a fraction (46%) is explained by the DNA size polymorphism. This suggests further heterogeneity relating to Lp(a) levels in the apo(a) gene.     

The plasminogen polymorphism in South African Negro populations: genetics and anthropogenetics

Summary Genetic polymorphism of human plasminogen (PLG) was investigated in 1252 unrelated individuals from eight South African Bantu-speaking Negro tribes. PLG phenotypes were determined by isoelectric focusing (pH 3.5–9.5 and 5–8 gradients) of neuraminidase-treated samples and subsequent detection by caseinolytic overlay or immunoblotting with specific antibody. No significant difference in the distribution of PLG alleles among the eight ethnic groups was observed. The combined allele frequencies of the common alleles in South African Negroes were 0.6977 for PLG*A, 0.2736 for PLG*B. In addition, six rare alleles were seen: PLG*A3, *A1, *M2, *B1, *B2, *B3. The rare variant PLG*B2 was proven to segregate by autosomal Mendelian inheritance in a family. The combined frequency for the rare alleles was 0.0287. The distribution of phenotypes in the total population sample was found to be in Hardy-Weinberg equilibrium. A striking difference in PLG allele distribution between Negroes from South Africa and published Negroid frequencies from North America could be observed. This difference was also seen in comparison with Mongoloid populations; in contrast, PLG frequencies for South African Negroes were similar or almost identical to known Caucasoid distributions.     

Genetic analysis of human lymphocyte proteins by two-dimensional gel electrophoresis

Summary We describe a genetic polymorphism of cytosol polypeptide with mol.wt. of 20,000 detected in lymphocytes the arythrocytes by two-dimensional gel electrophoresis. Three different electrophoretic phenotypes (type 1-1, 2-1, and 2-2) of the polypeptide have been identified in a Japanese population. Family studies indicate that the phenotypes are determined by two common alleles at a single autosomal locus. The polypeptide is present in the cytosol of various kinds of cells and is abundant in erythrocytes. The data on a gel filtration of the erythrocyte cytosol proteins on a Sephadex G-100 column suggest that the polypeptide exists as a dimer in cells. In nine out of 79 individuals, the phenotypes of the polypeptide were different from those of glyoxalase 1 (GLO1) which has similar properties in subunit size, cell distribution, and allele frequencies. These date indicate that the polypeptide with mol. wt. of 20,000 is a new polymorphic cellular polypeptide. We propose that the polypeptide be temporarily designated as cytosol polypeptide with mol. wt. of 20,000 (CP20) and that the gene for CP20 be designated as CP20. The gene frequencies of two common alleles (CP20 ¹ and CP20 ²) are 0.955 and 0.045, respectively, in a Japanese population.     

Molecular analysis of esterase D polymorphism

We have analyzed the esterase D (EsD) polymorphism at the nucleic acid level. Two common alleles, EsD¹ and EsD², are characterized by the substitution of one amino acid (Gly-to-Glu), which is caused by the point mutation of one nucleotide (G-to-A). Individuals exhibiting the EsD1 and EsD 2 phenotypes are homozygotes for EsD 1 and EsD 2 cDNAs, respectively. Individuals showing the EsD 2-1 phenotype have two kinds of cDNAs, viz., EsD 1 and EsD 2. The point mutation difference between the cDNAs of the EsD¹ and EsD² alleles results in a different SspI digestion site. A restriction fragment length polymorphism caused by this difference with respect to the SspI digestion site makes it possible to determine the EsD phenotype using DNA samples extracted from forensic materials with no EsD enzymatic activity.     

The distribution of Gc subtypes among the Mongoloid populations

The polymorphism of Gc (group-specific components) has been investigated for a series of 3,160 individual samples from 11 Mongoloid populations in Asia and North and South America by isoelectric focusing on polyacrylamide gels. The samples fall into six Gc phenotypes which can be explained by the three common alleles, Gc^1F, Gc^1S, and Gc², together with several variant phenotypes explained as the heterozygotes for the three common alleles. The distribution of Gc^1F suballele appears to be considerably different from population to population among Mongoloids, ranging from 0.105 (Machiguenga Indans, Peru) to 0.609 (Kadazan, Borneo). A clear geographic cline from Southeast Asia into South America in Gc^1F allele was observed in the populations. In general, Gc^1F allele frequencies are lower in European populations and higher in African populations. The range of variability in the Gc^1F values observed among the Asiatic populations is between the Africans and the Europeans.     

Genetic polymorphism of human complement component C81 in the Japanese population

Summary Genetic polymorphism of human C81 has been investigated using polyacrylamide gel isoelectric focusing (PAGIEF) in the presence of 3.1 M urea followed by electroblotting with enzyme immunoassay. In 448 individuals phenotypes of C81 were classified into three common and four rare patterns, and these were considered to be controlled by two common alleles, C81^*A and C81^* B, and three rare alleles which were tentatively designated C81^*A1J and C81^*A2J for acidic variants and C81^*B1J for the basic variant. The alleles of C81^*A2J and C81^*B1J are new rare alleles, but C81^*A1J might correspond to C81^*A1 in the former studies. Family data were in accordance with the hereditary rules. The gene frequencies were estimated as C81^*A is 0.6228, C81^*B is 0.3672, C81^*A1J is 0.0078, C81^*A2J is 0.0011, and C81^*B1J is 0.0011, respectively. The gene frequencies of the two common alleles agreed approximately with other ethnic groups. PAGIEF of neuraminidase-treated plasma samples followed by electroblotting with enzyme immunoassay is applicable to the study of heterogeneity of C81.     

Genetic polymorphism of human urine deoxyribonuclease I

Summary A genetic polymorphism of human urine deoxyribonuclease I (DNase I) has been detected by the technique of polyacrylamide gel isoelectric focusing (IEF-PAGE) followed by immunoblotting with anti-DNase I antibody. Family studies showed that the three common phenotypes —DNASE1 1, 1–2, and 2 — and the other four rare phenotypes — DNASE1 1–3, 2–3, 2–4, and 3–4 — represent homozygosity or heterozygosity for four autosomal codominant alleles, DNASE1 ^* 1, ^* 2, ^* 3, and ^* 4. The frequencies of the DNASE1 ^* 1, DNASE1 ^* 2, DNASE1 ^* 3, and DNASE1 ^* 4 alleles in a studied Japanese population were 0.5453, 0.4396, 0.0117, and 0.0034, respectively.     

Common chimpanzees have greater diversity than humans at two of the three highly polymorphic MHC class I genes

 MHC class I polymorphism improves the defense of vertebrate species against viruses and other intracellular pathogens. To see how polymorphism at the same class I genes can evolve in different species we compared the MHC-A, MHC-B, and MHC-C loci of common chimpanzees and humans. Diversity in 23 Patr-A, 32 Patr-B, and 18 Patr-C alleles obtained from study of 48 chimpanzees was compared to diversity in 66 HLA-A, 149 HLA-B, and 41 HLA-C alleles obtained from a study of over 1 million humans. At each locus, alleles group hierarchically into families and then lineages. No alleles or families are shared by the two species, commonality being seen only at the lineage level. The overall nucleotide sequence diversity of MHC class I is estimated to be greater for modern chimpanzees than humans. Considering the numbers of lineages, families, and alleles, Patr-B and Patr-C have greater diversity than the HLA-B and HLA-C, respectively. In contrast, Patr-A has less polymorphism than HLA-A, due to the absence of A2 lineage alleles. The results are consistent with ancestral humans having passed through a narrower population bottleneck than chimpanzees, and with pathogen-mediated selection having favored either preservation of A2 lineage alleles on the human line and/or their extinction on the chimpanzee line. Received: 8 December 1999 / Accepted: 30 December 1999     

A common haplotype of <Emphasis Type="Italic">DRD3</Emphasis> affected by recent positive selection is associated with protection from schizophrenia

The number and frequency of susceptibility alleles at loci associated to most psychiatric disorders is largely unknown, in spite of its relevance for the design of studies aiming to find these alleles. Both, common polymorphisms and rare mutations may contribute to the genetic susceptibility to complex psychiatric disorders, being the relative relevance of each type of variation currently under debate. Here, we confirmed the existence of a common protective haplotype against schizophrenia at the dopamine D₃ receptor (DRD3) gene, by replication and pooled analysis with previous data (Mantel–Haenszel χ² P value = 0.00227; OR = 0.79, 95% CI 0.68–0.92, based on 794 cases and 1,078 controls from three independent populations of European origin). This protective haplotype is at very low frequency in Sub-Saharan Africans (median 0.06) and at intermediate frequencies in other populations (median 0.25). We also revealed, by examining the patterns of linkage disequilibrium around this gene, that the protective haplotype has reached high frequency in non-African populations due to selection acting, most probably, on a linked functional polymorphism, the non-synonymous single nucleotide polymorphism Ser9Gly (rs6280), also at DRD3. Thus, this finding shows that the natural selection may play a role in the existence of common alleles conferring different susceptibility to schizophrenia. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A genetic polymorphism of the complement component factor B in chickens not linked to the Major Histocompatibility Complex (MHC)

The complement component factor B in chickens exhibits a genetic polymorphism with three common phenotypes, F, F/S, and S. These phenotypes segregate in flocks of chickens homozygous for the MHC (B complex) of the chicken. Furthermore, a genetic analysis has shown that the described factor B polymorphism is not linked to the B complex. It is not known whether the molecular basis for this polymorphism is due to the existence of allelic forms of the structural gene or to some posttranslational modifications, but the finding is discussed in view of the, close linkage of factor B polymorphism with the MHC of all mammalian species investigated so far.     

Genetic analysis of human lymphocyte proteins by two-dimensional gel electrophoresis

Summary We describe a genetic polymorphism of cytosol polypeptide with mol. wt. of 38,000 detected in phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes by two-dimensional gel electrophoresis. Three different electrophoretic phenotypes (type 1-1, 2-1, 2-2) of the polypeptide have been identified in a Japanese population. Family and population studies indicate that three phenotypes are determined by two common alleles at a single autosomal locus. Since the polypeptide is mainly present in cytosol of cells, we propose that the polypeptide be temporarily designated as cytosol polypeptide with mol. wt. of 38,000 (CP 38) and that the gene for CP 38 be designated as CP 38. The gene frequencies of two common alleles (CP 38 ¹ and CP 38 ²) are 0.899 and 0.101, respectively, in a Japanese population. The data on gel filtration of cytosol proteins on a Sephadex G-100 column suggest that CP 38 exists as a dimer in the cytosol. CP 38 was observed in the wide range of different cells, including B-lymphoblastoid cells, adult skin fibroblasts, HeLa cells, and erythrocytes. In 11 out of 72 individuals, the phenotypes of CP 38 were different from those of adenosine deaminase which is similar to CP 38 in subunit size, cell distribution, and allele frequencies. These data indicate that CP 38 is a new polymorphic polypeptide encoded by an autosomal locus.     

Polymorphism in a casein fraction of sows' milk

Polyacrylamide vertical gel electrophoresis was used to separate the caseins of sows' milk. Polymorphism was found in a region of the gels designated Cn₃. The Cn₃ polymorphism consists of two bands which appear to be controlled by two codominant alleles designated Cn ₃ ^A and Cn ₃ ^B . Homozygotes possess one band and heterozygotes posses both bands of equal intensity giving the following phenotypes: Cn₃A, Cn₃AB, and Cn₃B. A chi-square test for goodness of fit of the observed phenotypes to that expected by the Hardy-Weinberg equilibrium formula and a segregation analysis of eight matings involving 19 female progeny conform to the hypothesis that the Cn₃ polymorphism is controlled by two codominant autosomal alleles. Further family studies will be necessary to confirm the genetic control of the Cn₃ polymorphism.Deceased.     

The polymorphism of the plasma inter-α-trypsin inhibitor (ITI) and its relationship to the heavy chain H1 subunit gene (ITIH1) at 3p211-212

We investigated the ITI protein polymorphism in linkage analysis, usingDraI andSstI as restriction fragment length polymorphism (RFLP) markers for the ITIH1 gene. Isoelectric focusing (IEF) classification from 76 individual plasma samples and RFLP analysis from the corresponding DNA preparations disclosed linkage disequilibrium between the phenotypic IEF patterns of the two common ITI alleles, ITI^*1 and ITI^*2, and the diallelic DNA polymorphisms of two ITIH1 RFLPs, represented byDraI 4.0 kb andDraI 2.4 + 1.6 kb, and bySstI 6.7 kb andSstI 6.0 + 0.7 kb, for the ITI 1 and ITI 2 IEF phenotypes, respectively, and byDraI 4.0/2.4 + 1.6 kb andSstI 6.7/6.0 + 0.7 kb for the heterozygous ITI 1–2 IEF phenotype. Linked segregation between either of the RFLPs and the polymorphic ITI plasma protein locus has been established in nine informative family pedigrees. The less frequent allele in Europeans, ITI^*3, is not represented by a further allelic restriction fragment in either RFLP. The significant linkage disequilibrium observed in this genetic study indicates that the ITI locus, with the alleles ITI^*1 and ITI^*2, must be close to, or reside within, the ITIH1 gene. The diallelic ITI protein polymorphism therefore provides an informative phenotypic marker system for chromosome 3p211-212.     

Rare phenotypes of placental alkaline phosphatase an analysis of relationships with some neonatal and maternal variables

Summary Placental alkaline phosphatase (Pl) polymorphism is due to the occurrence of three common alleles and more than fifteen rare ones at an autosomal locus. The high number and frequency (about 2%) of rare Pl alleles represent a very special case among polymorphic enzymes. Since the Pl gene is also special in that it is active only during intrauterine life, the allelic diversity and its maintenance may be connected with intrauterine environment and with fetal development.This study embraced 502 consecutive newborn infants from the white population of European descent of New Haven (Connecticut). Analysis of the relationship between rare Pl phenotypes and the following variables was carried out: gestational length, birth weight, maternal age, birth order, sex, fetal and maternal AB0 and Rh phenotypes, feto-maternal AB0 and Rh compatibility status, and previous spontaneous abortions.The results indicate a negative association of Pl rate types with the 0 phenotype in the mother and with male sex of the infant.The present data suggest that interactions with sex and with the AB0 system during intrauterine life may contribute to the maintenance of allelic, diversity in Pl system.     

Genetic variation in the genus Bufo I. An extreme degree of transferrin and albumin polymorphism in a population of the American toad (Bufo americanus)

A population of Bufo americanus from southwestern Ohio exhibited an extreme degree of transferrin and albumin polymorphism. One hundred and eighty-five individuals were collected from this population, and their transferrin and albumin phenotypes were determined by vertical acrylamide gel electrophoresis. Thirteen transferrin alleles were present in 36 phenotypes, and 11 albumin alleles were present in 29 phenotypes. A deficiency of heterozygotes occurred at both protein loci. The possible mechanisms responsible for the polymorphism and deficiency of heterozygotes are discussed.This work was supported by grants from the following agencies to the Senior author: NSF GB23601, Society of the Sigma Xi, and the American Philosophical Society. Miami University contributed the computer and audiovisual services.     

A “new” genetic polymorphism of a human serum protein: inter-alpha-trypsin-inhibitor

Summary A new genetic polymorphism of a human serum glycoprotein, the inter--trypsin-inhibitor (ITI), has been demonstrated by population and family studies. Sera were examined after neuraminidase treatment by isoelectric focusing on agarose gels followed by immunoblotting or by immunfixation with specific ITI-antiserum. Using this method, three common ITI phenotypes 1, 1–2 and 2, as well as two further rare ITI types 1–3 and 2–3 were disclosed. Genetically, these phenotypes are controlled by three allelic genes that determine a total of six phenotypes. These alleles are designated ITI^*1, ITI^*2 and ITI^*3. The homozygous form of the third allele ITI^*3 has not been found, as yet. The frequencies of ITI were examined in two population samples from Southern Germany (n=248) and from Tyrol, Austria (n=124). The gene frequencies of the common alleles ITI^*1 and ITI^*2 were 0.575 and 0.417, respectively, in Southern Germany, and 0.577 and 0.423, respectively, in Tyrol, Austria. The third allele ITI^*3 was found only in the sample from Southern Germany, thus far, and was calculated to be 0.008.     

Phenotypic polymorphism and allele differentiation of isozymes in fodder beet,multigerm sugar beet and monogerm sugar beet

Summary Thirteen enzymes (MDH, SDH, LAP, PGM, PX, IDH, GPI, 6PGD, APH, GOT, GDH, ME and SOD) of 3 cultivated beet (B. vulgaris L.) gene pools, comprising 12 accessions of fodder beet, 11 of old multigerm sugar beet and 10 of modern monogerm sugar beet, were investigated using horizontal starch gel electrophoresis. Eleven accessions of primitive or wild B. vulgaris were also included for the comparison of isozymes. Variation in isozyme phenotypes was investigated to detect diversity in the three cultivated forms of beet. Phenotypic variation was observed in all except ME and SOD, which were monomorphic. A high degree of phenotypic polymorphism (Pj) was found in GDH, PGM, IDH, APH and MDH. Differences in phenotypic polymorphism in MDH, GPI and PX were recognized between fodder beet and both sugar beet groups. Average polymorphism for 13 enzymes in both sugar beets was significantly higher than that in fodder beet. For 13 enzymes, the existence of high isozyme diversity in both sugar beet gene pools was revealed. Allele frequencies in 13 alleles of five enzyme-coding loci, Lap, Px-1, Aph-1, Got-2 and Gdh-2, were investigated. New alleles, Px-1 ¹ and Got-2 ¹, were found in fodder beet accessions. No significant differences of average allele frequencies of five loci between fodder beet and both sugar beets were recognized. Several unique alleles and different isozyme phenotypes were observed in the accessions of B. vulgaris ssp. macrocarpa and ssp. adanensis. Future utilization of cultivated beet gene pools for sugar beet breeding is discussed from the viewpoint of genetic resources.