Haptoglobin gene subtypes in three Brazilian population groups of different ethnicities

Haptoglobin is a plasma hemoglobin-binding protein that limits iron loss during normal erythrocyte turnover and hemolysis, thereby preventing oxidative damage mediated by iron excess in the circulation. Haptoglobin polymorphism in humans, characterized by the Hp(*1) and Hp (*2) alleles, results in distinct phenotypes known as Hp1-1, Hp2-1 and Hp2-2, whose frequencies vary according to the ethnic origin of the population. The Hp(*1) allele has two subtypes, Hp (*1F) and Hp (*1S) , that also vary in their frequencies among populations worldwide. In this work, we examined the distribution frequencies of haptoglobin subtypes in three Brazilian population groups of different ethnicities. The haptoglobin genotypes of Kayabi Amerindians (n = 56), Kalunga Afro-descendants (n = 70) and an urban population (n = 132) were determined by allele-specific PCR. The Hp(*1F) allele frequency was highest in Kalunga (29.3%) and lowest in Kayabi (2.6%). The Hp(*1F)/Hp(*1S) allele frequency ratios were 0.6, 1.0 and 0.26 for the Kayabi, Kalunga and urban populations, respectively. This variation was attributable largely to the Hp(*1F) allele. However, despite the large variation in Hp(*1F) frequencies, results of F (ST) (0.0291) indicated slight genetic differentiation among subpopulations of the general Brazilian population studied here. This is the first Brazilian report of variations in the Hp(*1F) and Hp(*1S) frequencies among non-Amerindian Brazilians.     

Haplotype analysis of the apolipoprotein E and apolipoprotein C1 loci in Portugal and São Tomé e Príncipe (Gulf of Guinea): linkage disequilibrium evidence that APOE*4 is the ancestral APOE allele

The joint distributions of phenotypes from the apolipoprotein E gene (APOE) and from a closely linked restriction site polymorphism at the apolipoprotein C1 locus (APOC1) were studied in population samples from Portugal and S?o Tomé e Príncipe (Gulf of Guinea), a former Portuguese colony that was originally populated by slaves imported from the African mainland. The frequencies of the APOE alleles (*2, *3, and *4) in Portugal and S?o Tomé fitted the ranges of variation generally observed in European and African populations, respectively. Haplotype analysis showed that in both populations the strength of linkage disequilibrium was highest for the APOE*2 allele and lowest for the APOE*4 allele, suggesting that the origin of the APOE alleles followed a 4-->3-->2 pathway and thus providing independent confirmation of the results from sequence homology studies with nonhuman primates. In accordance with global trends in the distribution of human genetic variation, the European sample from Portugal presented more intense linkage disequilibrium between APOE and APOC1 than the African sample from S?o Tomé where, despite the short 4-kb distance that separates the 2 loci, the level of association between the APOC1 alleles and APOE*4 was nonsignificant.     

Genetic factors of predisposition to endometriosis and response to its treatment]

The relative frequencies of the normal (+) and null (0) alleles of the glutathione-S-transferase M1 (GSTM1) gene, as well as those of the rapid (R) and slow (S) forms of N-acetyl transferase 2 (NAT-2), were studied in the Russian and French populations and in endometriosis (EM) patients. In the total Russian and French populations, the proportions of homozygotes for deletion in gene GstM1 (0/0) were 42.2 and 45.8%, respectively, whereas in Russian and French EM patients, these values were 58.6 and 76.9%, respectively. The differences in these proportions between the total population and subjects with EM were significant at the confidence levels of 0.98 (chi 2 = 5.45; P < 0.02) and 0.90 (chi 2 = 3.01; P < 0.1) for the French and Russian populations, respectively. The frequencies of allele S of the Nat-2 gene were also similar in the Russian and French populations (60 and 63.1%, respectively), with these frequencies being somewhat higher in EM patients (71.2 and 77.7%, respectively). In Russians, the proportion of EM patients who were homozygous for the R form of NAT-2 (R/R) was significantly lower (chi 2 = 5.1). Forty-three of the patients with external genital EM received complex treatment with the use of the interferon inducer Cyclopheron. In 17 patients, a pronounced positive dynamics was observed, and 29 patients exhibited an increased resistance to the immunomodulating therapy. These groups comprised 1 and 25 GstM1 0/0 homozygotes, respectively; the number of patients with the slow NAT-2 form was 13 (7 S/S and 6 S/R genotypes) and 29 (20 S/S and 9 S/R genotypes), respectively. The obtained data indicate that the GstM1 and Nat-2 genes are involved in the EM pathogenesis. Therefore, molecular screening for the GstM1 0 and Nat-2 S alleles would be a good prognostic test when prescribing the postoperative treatment for EM and predicting its effectiveness.     

Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample

Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure. In addition to cytochrome P450 2D6, which plays a critical role in drug metabolism, ABCB1 encoded P‐glycoprotein (PGP) is also an important determinant in drug bioavailability. The genes encoding these molecules are highly variable among populations and, given their clinical importance in drug therapy, determining CYP2D6 and ABCB1 allele frequencies in specific populations is very important for useful application in clinical settings. In this study the frequency of the pharmacologically relevant CYP2D6*3, *4, *5, *6 allelic variants and gene duplication, and ABCB1 C1236T and C3435T gene polymorphisms and their haplotypes was determined in a population sample of 100 Portuguese healthy subjects. CYP2D6 allele frequencies were 1.4% (*3), 13.3% (*4), 2.8% (*5), 1.8% (*6) and 6.1% (gene duplication), with 5% of the individuals classified as PM and 8.4% as UM. The frequencies obtained for the non‐functional alleles and for the CYP2D6 gene duplication are in agreement with other South European populations, and reinforce the previously suggested south/north gradient of CYP2D6 duplications. Allelic frequencies for the ABCB1 polymorphisms were 52% (3435C) and 54% (1236C) and the most common haplotype (1236C‐3435C) occurred with a frequency of 45.5%. Although allele and haplotype frequency data for ABCB1 in Southern Europe is limited, some discrepancies were found with other European populations, with possible therapeutic implications for PGP substrate drugs. Copyright © 2009 John Wiley & Sons, Ltd.     

Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population

Drug metabolizing enzymes participate in the neutralizing of xenobiotics and biotransformation of drugs. Human cytochrome P450, particularly CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, play an important role in drug metabolism. The genes encoding the CYP enzymes are polymorphic, and extensive data have shown that certain alleles confer reduced enzymatic function. The goal of this study was to determine the frequencies of important allelic variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 in the Jordanian population and compare them with the frequency in other ethnic groups. Genotyping of CYP1A1(m1 and m2), CYP2C9 (*2 and *3), CYP2C19 (*2 and *3), CYP3A4*5, CYP3A5 (*3 and *6), was carried out on Jordanian subjects. Different variants allele were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). CYP1A1 allele frequencies in 290 subjects were 0.764 for CYP1A1*1, 0.165 for CYP1A1*2A and 0.071 for CYP1A1*2C. CYP2C9 allele frequencies in 263 subjects were 0.797 for CYP2C9*1, 0.135 for CYP2C9*2 and 0.068 for CYP2C9*3. For CYP2C19, the frequencies of the wild type (CYP2C19*1) and the nonfunctional (*2 and *3) alleles were 0.877, 0.123 and 0, respectively. Five subjects (3.16?%) were homozygous for *2/*2. Regarding CYP3A4*1B, only 12 subjects out of 173 subjects (6.9?%) were heterozygote with none were mutant for this polymorphism. With respect to CYP3A5, 229 were analyzed, frequencies of CYP3A5*1,*3 and *6 were 0.071, 0.925 and 0.0022, respectively. Comparing our data with that obtained in several Caucasian, African-American and Asian populations, Jordanians are most similar to Caucasians with regard to allelic frequencies of the tested variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.     

Proteomic analysis of plasma from patients with systemic lupus erythematosus: increased presence of haptoglobin alpha2 polypeptide chains over the alpha1 isoforms

In the present study plasma samples from 15 systemic lupus erythematosus (SLE) patients and 16 healthy controls of initially unknown haptoglobin (Hp) phenotype were separated by 2-DE, and tryptic digests of the excised Hpalpha polypeptide chain spots were analyzed by MALDI-TOF-MS. Selected tryptic peptides were sequenced by nano-(n)ESI-IT MS/MS. The six major Hp phenotypes were present, although with distinct frequencies in controls and SLE patients. Thus, there were an increased proportion of SLE patients with Hp 2-2, or Hp 2-1S phenotypes. The Hp phenotype distribution resulted in allele frequencies of 0 625 (Hp(2)), 0.281 (Hp(1S)), and 0.093 (Hp(1F)) in healthy controls, correlating fairly well with the allele frequencies of European populations. In contrast, the Hp allele frequencies of the SLE patients were 0.733 (Hp(2)), 0.233 (Hp(1S)), and 0.033 (Hp1(1F)), which clearly indicated an increased frequency of Hp(2), a similar proportion of Hp(1S) and a diminished proportion of Hp(1F) in SLE patients compared with that in healthy controls. Preferential Hpalpha2 expression in SLE patients may contribute to some of the clinical manifestations of the disease such as hypergammaglobulinemia, systemic vasculitis, and cardiovascular disorders.     

Molecular genetic diversity in 5 populations of Madhya Pradesh, India

This paper presents data on the distribution of 3 amplified fragment length polymorphisms (D1S80, APOB, and YNZ22) in 5 populations of Central India. Using the polymerase chain reaction technique, 3 caste (Brahmin, Khatri, and Dhimer) and 2 tribal (Gond and Baiga) populations were studied for the 3 loci. The allelic variations observed in the caste populations are compatible with those of many Caucasian populations, but the caste populations showed significant overall and interpopulation variability within the region. D1S80 allele *24 varied from 32% (Dhimers) to 42% (Brahmins). Allele *18 was not observed in Baiga tribal populations, but in caste populations it varied from 11% (Dhimers) to 24% (Brahmins). Both tribal populations showed higher frequencies of allele *31 (17%-18%). For APOB, caste populations again showed bimodal distribution of alleles *35 and *37, but in tribal populations higher allele numbers (*47, *49) were also frequent. For YNZ22, extensive variation was observed for all populations studied. Allele *4 was the most common in caste populations, while alleles *2, *7, and *10 were prominent in tribal populations. The level of gene differentiation is not very high for the 3 systems studied in the 5 populations. Overall, allele frequency distribution, heterozygosity, and genetic diversity analysis show that the genetic diversity observed is socially and geographically structured.     

A population genetic characterization of Estonians

This paper discusses the genetic characterization of Estonians on the basis of eight blood group systems, and the traits of PTC tasting and colour blindness in 40 Estonian population samples from various parts of the country. The allele frequencies for the total Estonian population and for the four most different regions are presented. The survey shows genetic heterogeneity within the Estonians; the greatest genetic differences were observed in West-East direction. The West-Islands, West, and North Estonia differ from the other regions (East, South-East, also South-West and Central Estonia--which form a compact cluster). The mean allele frequencies of the Estonians are comparable to those typical for populations from North and East Europe, but the allele frequencies of Estonians are characterized by tendencies in two opposite (western and eastern) directions, like in other Finno-Ugric populations and concerning other anthropological traits. Estonians reveal closest similarities to the nearest neighbouring populations, regardless of their language group. The genetic heterogeneity and antagonistic traits in Estonians seem to be traces of the original genetic structure of Finno-Ugric ancestor populations which were neither Mongoloid nor Caucasoid.     

Polymorphisms of the haptoglobin peptide chains in Pyrenean populations.

This study has analyzed the haptoglobin genotype frequencies in over 900 samples from populations living on the Northern slopes of the Pyrenees. The results emphasize the importance of systematically determining the frequencies of the Hp1S, Hp1F, Hp2SS, Hp2FF, Hp2FS alleles. Hp1S was the predominant allele, the HpIS/Hp1 distribution varying between .5 and .69 as in most European populations. Hp2 alleles were observed in low frequency with differences in geographically distinct samples. Pyrenean populations in the western zones (Basques and Baronnies) were found to contain the Hp2FF allele while those in eastern regions, the Hp2SS allele. We have speculated that Hp2SS is as old as the Hp2FF, arising from southern Mediterranean areas, and suggest that Pyrenean groups have different origins.     

haplotypes identified by DNA polymorphisms at the apolipoprotein A-1 and C-III loci and hypertriglyceridaemia

Summary A Japanese group comprising 40 hypertriglyceridaemic and 35 normolipidaemic subjects were genotyped for two intragenic DNA restriction fragment length polymorphisms (RFLPs) at the A-1 and C-III gene loci. An Sst-1 polymorphism is located at the 3 end of the C-III gene and a Msp-1 polymorphism in the third intron of the A-1 gene. The polymorphic restriction sites are 3.8kb apart. The polymorphism with Sst-1 was present at allelic frequencies of 0.67 (S1 allele) and 0.33 (S2 allele), and the polymorphism with Msp-1 was present at allelic frequencies of 0.55 (M1 allele) and 0.45 (M2 allele). The alleles S1, S2, M1, and M2 are in linkage disequilibrium and three haplotypes were identified S1-M1, S1-M2, and S2-M2. Unlike the previously reported association of the S2 allele with hypertriglyceridaemia found in Caucasians there was no difference in the frequency of S2 allele between normolipidaemic and hyperlipidaemic Japanese. However one of the haplotypes S1-M2 was significantly increased in the hypertriglyceridaemic subjects (32% versus 11% P>0.025). Thus in Japanese there is an association with genotypes at this locus and hypertriglyceridaemia but with a different haplotype than in Caucasians.     

Polymorphism of the HFE gene associated with hereditary hemochromatosis in populations of Russia

Expression of hereditary hemochromatosis as well as predisposition to iron overload syndrome and sporadic porphyria cutanea tarda are currently believed to be associated with the inheritance of certain allelic variants of the HFE gene. Allele frequencies of the C282Y (845A) and H63D (187G) mutations in the HFE gene in human populations of different races are remarkably different, and the prevalence of the S65C (193T) mutation is still poorly studied. In the present study we estimated allele frequencies of HFE mutations in Russians and in a number of Siberian ethnic indigenous populations. In Russians, allele frequencies of the C282Y, H63D and S65C mutations were 3.7, 13.3 and 1.7%, respectively. These values were similar to those observed in populations of Europe. The C282Y mutation was not detected in the population samples of Siberian ethnic groups, including Mansis, Khantys (Finno-Ugric group), Altaians, and Nivkhs (Mongoloids), suggesting that the frequency of this allele in the populations examined was lower than 1%. The frequency of the C282Y allele in the Tuvinian and Chukchi samples (Mongoloids) constituted 0.45 and 0.8%, respectively. Furthermore, pedigree analysis of both Chukchi carriers discovered showed that some of their ancestors were from other ethnic groups. Low frequencies of this allelic variant is typical of many Eastern Asian populations, which are also characterized by rather low frequencies of the H63D variant. In contrast, in some ethnic groups of Western Siberia allelic frequency of the H63D mutation is rather high, constituting 8.7% in Altaians, 15.5% in Mansis, and 11.3% in Khantys. The frequency of this allele in Tuvinians, Nivkhs, and Chukchis constituted 5, 4.7, and 0.8%, respectively. These findings make it possible to estimate the proportion of individuals predisposed to iron overload syndrome in different Russian ethnic groups. The HFE allele frequency distribution patterns observed in the populations examined pointed to pre-Celtic appearance of the CY82 allele. It also provides elucidation of the evolutionary genetic relationships between Siberian ethnic groups and the contemporary populations of Eastern and Western Europe.     

Distribution of hereditary blood groups among indians in South America. VII. In Argentina

This seventh and last paper in a series on the distribution of blood groups among Indians in South America reports the findings among Amerinds in Argentina. Blood specimens were procured from putative full-bloods of the following tribes: 38 Diaguita (Calchaqui), 230 Mataco, 90 Chiriguano, 142 Choroti, 51 Toba, 120 Chané, 96 Chulupi (Ashluslay), and 178 Araucano (Mapuche). These 945 samples were tested for blood factors in the A-B-O, M-N-S-s, P, Rh-Hr, K-k, Lewis, Duffy, Kidd, and Diego systems. Serum samples were tested for haptoglobins and transferrins. Hemolysates prepared from whole blood were tested for hemoglobin types. The results are presented in tables as phenotype distribution and calculated allele frequencies. Locations of the populations from which blood samples were procured are shown on a map of North and Central Argentina. High frequencies are reported for the O allele. Allele frequencies are high also for M, s, R¹ (CDe), R² (cDE), k, Le^H and Fy. They are usually low or absent for alleles B, N, S, Mi^a, Vw, R^o (cDe), r (cde), K, Le¹, and fy. The Di allele ranged from 0.013 in the Araucano (Mapuche) to 0.192 in the Toba. Allele frequencies aberrant for Indians were observed more often in the Araucano (Mapuche) and Diaguita tribes, due probably to greater inflow of non-Indian genes into their gene pool and perhaps also to genetic drift in small inbred populations. Hp¹ allele frequencies varied from 0.43 in the Choroti to 0.80 in the Diaguita. All samples tested for transferrins except six contained the variant Tf C; the six were B₁ C present in samples from one Mataco and six Araucano persons. All the specimens tested electrophoretically for hemoglobin types contained only (A) as a major component.     

Pelage mutant allele frequencies in domestic cat populations of Poland

To determine mutant allele frequencies, surveys of coat phenotypes of the domestic cat (Felis catus L.) were conducted from October 1982 to June 1985 in 23 urban and rural populations of Poland (N = 67-278). The seven gene loci studied included: sex-linked orange (O), agouti (A), tabby (T), full-color expression (D), long hair (L), piebald spotting (S), and dominant white (W). The mutant allele frequencies at these loci are: p(O) = 0-0.139, q(a) = 0.487-0.774, p(Ta) = 0, q(tb) = 0.132-0.451, q(d) = 0-0.332, q(l) = 0-0.220, p(S) = 0.242-0.620, and p(W) = 0. The coefficients of darkness estimated ranged from 0.51 to 0.75, showing no statistically significant differences between urban and rural populations. Of the gene loci studied, only A and S show such differences, with the incidence of alleles a and S being, respectively, significantly higher and lower for urban areas. The relatively great amount of genetic heterogeneity in the cat populations of Poland seems to reflect historical determinants. The Polish data are compared to those from Europe, northern Africa, and western Asia, and geographic patterns in distribution for all of the mutant alleles studied are described.     

Apolipoprotein A1 gene polymorphisms at the -75 bp and +83/ 84 bp polymorphic sites in healthy Omanis compared with world populations

The relative frequencies of the *A allele of the APOA1 gene at -75 bp (M1-) and the C or T +83/+ 84 bp allele (M2-) varied significantly between populations. We found the frequencies of M1- and M2- to be 0.22 and 0.067, respectively, in 150 healthy Omanis. These frequencies were compared to frequencies found in other world populations.     

Allele and genotype frequencies of polymorphic FMO3 gene in two genetically distinct populations

The aims of this study were to analyze flavin-containing monooxygenase 3 (FMO3) polymorphisms and allele and genotype frequencies in 256 Han Chinese and 50 African-American individuals, to compare the allele and genotype frequencies of these populations with those of other world populations. For Han Chinese, genotyping of three common single nucleotide polymorphisms, E158K, V257M and E308G was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). For African-Americans, genotyping of all coding exons was performed by modified PCR-single strand conformational polymorphism (SSCP). Evolutionary rates of FMO3 were estimated computationally. We found that there were significant differences in allele and genotype frequencies among Han Chinese, African-Americans and other world populations. In Han Chinese, the minor allele frequencies (MAFs) were 0.229 (E158K), 0.203 (V257M) and 0.148 (E308G), respectively. In African-Americans, MAFs were 0.48 (E158K), 0.05 (V257M) and 0 (E308G), respectively. There was rapid evolution during the divergence of primate FMO3. This is the first report comparing FMO alleles and genotypes between Han Chinese and African-Americans. A Han Chinese population database has been established for three gene polymorphisms. The data presented here justify further pharmacogenetic studies for potentially optimizing recommended drug dosages and evaluating relationships with disease processes.     

Isolation by distance and selection effects on genetic structure of sardines Sardina pilchardus Walbaum

Allozyme data were used to analyse the genetic structure of Sardina pilchardus populations. Fifty samples from 15 locations between the North Sea and Mauritania, including samples from the Azores, Madeira and the Mediterranean Sea, were surveyed. A weak but significant structure was found between all samples ( F _ST= 0.057, P < 0·001). This structure results from a change in the most common allele of SOD* between the North African and the Azores populations separated by the greatest distance. This locus seemed to be under selective pressure according to the test of neutrality, and the variations in allele frequencies may be explained due to isolation by distance (IBD) of coastal populations (from Mauritania to the North Sea) ( r = 0·86, P < 0·001). When SOD* was removed from the analyses, IBD was not observed in coastal populations ( r = 0·236, P > 0·05) but was observed over the whole range ( r = 0·321, P = 0·05). The genetic structure of S. pilchardus is driven by both IBD and selective processes.     

Study of five haemogenetic markers (Gc, C3, Bf, Ag, and GALT) in six Indonesian populations and in 12 subgroups of Balinese

In various ethnic groups of the Indonesian archipelago and of Bali, the polymorphisms of the serum proteins Gc globulin (vitamin D-binding protein), C3 (complement component 3), Bf (complement factor B), Ag x,y (lipoprotein allotypes), and of the red cell enzyme system GALT (galactose-1P-uridyltransferase) were analysed. Among the studied proteins, the Gc system was the most informative one for the anthropologist. Besides considerable differences of frequencies of the common alleles Gc*1F, Gc*1S and Gc*2, a number of rare alleles (1A1, 1A3, 1A8, 1A9, 1A12, 1C2, 1C21, 1C24, and 2C8) and some new ones (1C28, 1C29, 1C30, 2C9) were observed. The presence of Gc*1A1 demonstrates the relationship to the Australo-Melanesian populations, but Mongolian variants (1A3, 1A8, 1A9, 1C2) were also encountered. Within the C3 system a very high frequency of the C3*S allele was observed in all populations. The rare alleles C3*F0.55, C3S1, and C3*S0.5 were observed in some groups. A new allele (C3*F0.35) was detected in a Chinese individual and in a nobleman from Bali. The frequency of the Bf*F allele was rather low in general, and the Bf*S0.7 allele was found in three Indonesian individuals only. The Ag*(x) frequencies were rather high, as it is known for Asiatic populations. Variability among subgroups was not very pronounced. The GALT*2 allele (Duarte variant of the enzyme) was observed very rarely; however, it was present in several populations. Enzyme activities could not be determined, and therefore we cannot tell whether the galactosaemia gene (GALT*0) was present or not.     

Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.     

Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences.

Cytochrome P450 2D6 (CYP2D6) metabolizes many important drugs. CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles. Their frequencies were determined in 589 unrelated German volunteers and correlated with enzyme activity measured by phenotyping with dextromethorphan or debrisoquine. For genotyping, nested PCR-RFLP tests from a PCR amplificate of the entire CYP2D6 gene were developed. The frequency of the CYP2D6*1 allele coding for extensive metabolizer (EM) phenotype was .364. The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype [IM]) showed frequencies of .324, .018, and .015, respectively. By use of novel PCR tests for discrimination, CYP2D6 gene duplication alleles were found with frequencies of .005 (*1x2), .013 (*2x2), and .001 (*4x2). Frequencies of alleles with complete deficiency (poor metabolizer phenotype [PM]) were .207 (*4), .020 (*3 and *5), .009 (*6), and .001 (*7, *15, and *16). The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found. All 41 PMs (7.0%) in this sample were explained by five mutations detected by four PCR-RFLP tests, which may suffice, together with the gene duplication test, for clinical prediction of CYP2D6 capacity. Three novel variants of known CYP2D6 alleles were discovered: *1C (T1957C), *2B (additional C2558T), and *4E (additional C2938T). Analysis of variance showed significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) between carriers of EM/PM (mean MR = .006) and IM/PM (mean MR = .014) alleles and between carriers of one (mean MR = .009) and two (mean MR = .003) functional alleles. The results of this study provide a solid basis for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment.     

Response to natural and laboratory selection at the Drosophila hsp70 genes

Abstract.— To determine whether and how laboratory and natural selection act on the hsp70 (70-Kd heat-shock protein) genes of Drosophila melanogaster , we examined hsp70 allele frequencies in two sets of populations. First, five populations reared at different temperatures for more than 20 years differentially fixed both a large insertion/deletion (indel) polymorphism at the 87A7 hsp70 cluster ("56H8"/"122") and a single nucleotide polymorphism at the 87C1 hsp70 cluster. In both cases, the 18°C and 25°C populations fixed one allele and the 28°C populations the other, consistent with previously described evolved differences among these populations in Hsp70 expression and thermo-tolerance. Second, we examined 56H8 and 122 frequencies in a set of 11 populations founded from flies collected along a latitudinal transect of eastern Australia. The 56H8 allele frequencies are positively associated with latitude, consistent with maintenance of the 56H8/122 polymorphism by natural selection. Thermal extremes and average values are negatively correlated with latitude. These results suggest that natural selection imposed by temperature and thermal variability may affect hsp70 allele frequencies.