Genetic profile of cosmopolitan populations: effects of hidden subdivision

Natural populations of many organisms exhibit excess of rare alleles in comparison with the predictions of the neutral mutation hypothesis. It has been shown before that either a population bottleneck or the presence of slightly deleterious mutations can explain this phenomenon. A third explanation is presented in this work, showing that hidden subdivision within a population can also lead to an excess of rare alleles in the total population when the expectations of the neutral model are based on the allele frequency profile of the entire population data. With two examples (mitochondrial DNA-morph distribution and isozyme allele frequency distributions), it is shown that most cosmopolitan human populations exhibit excess of rare as well as total allele counts, when these are compared with the expectations of the neutral mutation hypothesis. The mitochondrial data demonstrate that such excesses can be detected from genetic variation at a single locus as well, and this is not due to stochastic error of allele frequency distributions. Contrast of the present observations with the allele frequency profiles in agglomerated tribal populations from South and Central America shows that even when the neutral expectations hold for individual subpopulations, if all subpopulations are grouped into a single population, the pooled data exhibit an excess of total number of alleles that is mainly due to the excess of rare alleles. Therefore, a primary cause of the excess number of rare alleles could be the hidden subdivision, and the magnitude of the excess indicates the extent of substructuring. The two components of hidden subdivision are: 1) Number of subpopulations, and 2) the average genetic distance among them. The implications of this observation in estimating mutation rate are discussed indicating the difficulties of comparing mutation rates from different population surveys.     

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.     

High-density single-nucleotide polymorphism maps of the human genome

Here we report a large, extensively characterized set of single-nucleotide polymorphisms (SNPs) covering the human genome. We determined the allele frequencies of 55,018 SNPs in African Americans, Asians (Japanese-Chinese), and European Americans as part of The SNP Consortium's Allele Frequency Project. A subset of 8333 SNPs was also characterized in Koreans. Because these SNPs were ascertained in the same way, the data set is particularly useful for modeling. Our results document that much genetic variation is shared among populations. For autosomes, some 44% of these SNPs have a minor allele frequency > or =10% in each population, and the average allele frequency differences between populations with different continental origins are less than 19%. However, the several percentage point allele frequency differences among the closely related Korean, Japanese, and Chinese populations suggest caution in using mixtures of well-established populations for case-control genetic studies of complex traits. We estimate that approximately 7% of these SNPs are private SNPs with minor allele frequencies <1%. A useful set of characterized SNPs with large allele frequency differences between populations (>60%) can be used for admixture studies. High-density maps of high-quality, characterized SNPs produced by this project are freely available.     

Ace Alu insertion polymorphism in Croatia and its isolates

Alu elements are a family of interspersed repeats in the genome propagating by retroposition into new chromosomal locations. Alu insertion in Ace gene is known to be polymorphic (presence/absence of Alu element) in worldwide populations and as such serves as marker for population structure analyses. In this study we examined the distribution of genotypes and allele frequencies of this polymorphism in general Croatian population and its two isolates (the island of Hvar and the coastal region of the Middle Dalmatia) and related them to the level of endogamy as an indicator of inbreeding in these populations. Results showed that these three population groups are different with respect to Ace Alu polymorphism. The endogamy was highest on the island of Hvar. With the increase of endogamy a decrease in heterozigosity was observed. The same trend was observed for the frequency of insertion allele. Its frequencies in the village subpopulations of two studied isolates are subject to genetic drift due to small population sizes and high levels of endogamy. This in turn causes genetic differentiation among villages that is observed to be higher on the island of Hvar than in the coastal region. In the worldwide perspective, the Ace Alu insertion allele frequency of 50.6% in the general Croatian population falls within the range of other European populations.     

Microsatellite variation at 24 STR loci in three endogamous groups of Uttar Pradesh,India

We have studied variation at 24 microsatellite markers among 50 individuals from each of three endogamous groups, Bhargavas, Chaturvedis, and non-Bhargava, non-Chaturvedi Brahmins of Uttar Pradesh, India. The number of alleles at the loci tested varied from 4 to 11, with an average of 6 at each locus. Heterozygosity was found to be quite high at all loci in the three subpopulations. It varied between 0.44 to 0.84 among Bhargavas (average 0.6510), 0.44 to 0.80 among Chaturvedis (average 0.6633 +/-), and 0.42 to 0.85 among Brahmins (average 6.694 +/-). Hardy-Weinberg equilibrium analysis revealed that these populations are under genetic equilibrium at almost all the loci tested. Comparisons of allele frequency between Bhargavas and Chaturvedis showed that they differed significantly at 14 short tandem repeat (STR) markers (p < 0.001), while Chaturvedis and Brahmins differed at 6 (p < 0.05) and Brahmins and Bhargavas at 8 (p < 0.05). Average F(IS) and F(ST) for the 24 STR markers was -0.02 and 0.013, respectively. We used both un-weighted pair group with arithmetic mean and principal components analysis to evaluate genetic distances among the three groups. Our results revealed that although there were differences at particular allele frequencies between Bhargavas vs. Brahmins, Bhargavas vs. Chaturvedis, and Brahmins vs. Chaturvedis, these differences were not statistically significant when combined over all 24 STR markers between Chaturvedis vs. Brahmins and Bhargavas vs. Brahmins. The genetic distance analysis revealed that Bhargavas are slightly apart from the other two populations.     

POPULATION STRUCTURE AND GENETIC DIFFERENTIATION IN NATIVE AND INTRODUCED POPULATIONS OF DESCHAMPSIA CAESPITOSA (POACEAE) IN THE COLORADO ALPINE

Deschampsia caespitosa is a widespread grass common in moist areas of the alpine tundra of the Rocky Mountains. Enzyme electrophoresis was used to examine population genetic structure along two soil moisture gradients in Rocky Mountain National Park, Colorado. Introduced plants used in a revegetation project were also sampled at one of the sites. At both sites, there were significant differences among subpopulations in allele frequencies, but these differences were distributed in a patchy fashion and were not correlated with the apparent soil moisture gradients. The degree of genetic subdivision differed between the two sites. At one site, gene flow appeared to be high and differences in allele frequencies are attributed to selection in a mosaic environment. At the other site, gene flow appeared more restricted and differences in allele frequencies between subpopulations are attributed to selection and limited gene flow acting simultaneously. Overall, 15% of the genetic variability is between subpopulations and gene flow is high, even between subpopulations separated by up to 1.5 km, but local conditions can apparently limit gene flow and increase the degree of genetic subdivision. The mean genetic distance between introduced plants and the native subpopulations was significantly higher than the mean genetic distance between all other subpopulations. Despite the high gene flow apparent in alpine tundra subpopulations of Deschampsia caespitosa, significant genetic structuring of these subpopulations has developed.     

Comparison of VNTR allele frequencies and inclusion probabilities over six populations

There is considerable debate about the methodologies used to estimate VNTR (Variable Number of Tandem Repeats) multi-locus genotype frequencies or odds of inclusion in forensic cases. To compare two of the methods in use, allele frequency distributions among six populations were compared and the effect of population heterogeneity on VNTR multi-locus genotype frequency estimation was examined. Genotype frequencies estimated from single population data were one or two orders of magnitude smaller than those estimated by picking the highest allele frequency in a group of subpopulations to estimate genotype frequencies using a ceiling principle. The average change does not appear to be very sensitive to the set of subpopulations used; four locus frequencies still give inclusion odds of one in a million or less. We think that use of the ceiling principle solves both the statistical problem engendered by subpopulation heterogeneity and the legal problem of assuming that the prepetrator and suspect belong to the same subpopulation. The counterintuitive fact of human genetic polymorphism is that it is easier to identify an individual than it is to identify the subpopulation, ethnic group or race to which that individual belongs.     

The many-demes limit for selection and drift in a subdivided population

A diffusion approximation is obtained for the frequency of a selected allele in a population comprised of many subpopulations or demes. The form of the diffusion is equivalent to that for an unstructured population, except that it occurs on a longer time scale when migration among demes is restricted. This many-demes diffusion limit relies on the collection of demes always being in statistical equilibrium with respect to migration and drift for a given allele frequency in the total population. Selection is assumed to be weak, in inverse proportion to the number of demes, and the results hold for any deme sizes and migration rates greater than zero. The distribution of allele frequencies among demes is also described.     

Frequency and fitness cost of resistance to Bacillus thuringiensis in Chrysomela tremulae (Coleoptera: Chrysomelidae)

The "high dose-refuge" (HDR) strategy is commonly recommended and currently used for delaying or preventing pest adaptation to transgenic plants producing Bacillus thuringiensis (Bt) toxins. The efficiency of this strategy depends, among other factors, on the initial frequency of Bt resistance alleles and on the fitness costs associated with these alleles. Two years ago, an allele conferring resistance to Bt poplar was detected in a French population of the poplar pest Chrysomela tremulae F. Although this pest had never been subjected to Bt selection pressure due to human activities, the frequency of this allele was estimated at 0.0037, with a 95% credible (CI) interval of 0.00045-0.0080. We investigated the frequency of this allele in a second sample of C. tremulae collected more than 500 km from the site of the initial population. The estimated frequency in this sample was 0.0113 (95% CI 0.0031-0.0247), reinforcing the conclusion that resistance to Bt plants may be present at detectable frequencies in pest populations before selection resulting from pest management by humans. The frequency of the Bt resistance allele over the two samples was 0.0049 (95% CI 0.0020-0.0091). We also followed five laboratory lines in which the frequency of this allele was initially fixed at 0.500. After five generations maintained on non-Bt poplar leaves, the frequency of this allele decreased in all lines, whereas allelic frequencies at a neutral locus were unaffected. Thus, the Bt resistance allele detected in French populations of C. tremulae is probably associated with a fitness cost.     

The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations.

Application of uniform methods for measuring the apolipoprotein (apo) E polymorphism and plasma cholesterol levels in nine populations (Tyrolean, Sudanese, Indian, Chinese, Japanese, Hungarian, Icelandic, Finnish, and Malay) revealed significant heterogeneity among them in apo E type frequencies and mean cholesterol levels. The major apo E types in all populations were E3/2 (frequency range from 7.0% in Indians to 16.9% in Malays), E3/3 (frequency range from 39.8% in Sudanese to 72.1% in Japanese), and E3/4 (frequency range from 11.3% in Japanese to 35.9% in Sudanese). Mean cholesterol levels ranged from 144.2 mg/dl in the Sudanese to 228.5 mg/dl in the Icelandics. Two-way analysis of variance of the effect of population and apo E type on cholesterol levels showed no significantly interaction effect, indicating that the effects of apo E type on cholesterol levels do not differ significantly among the populations. The overall average excess for the epsilon 2 allele was -14.12 mg/dl (range -31.63 to -8.82 mg/dl); for the epsilon 3 allele, 0.04 mg/dl (range -1.87 to 1.58 mg/dl; and for the epsilon 4 allele, 8.14 mg/dl (range -1.71 to 13.31 mg/dl). Despite the apparent heterogeneity in these values, especially for the epsilon 4 allele, comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations. These data indicate that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors.     

Mosaic microecological differential stress causes adaptive microsatellite divergence in wild barley, Hordeum spontaneum, at Neve Yaar, Israel.

Genetic diversity at 38 microsatellite (short sequence repeats (SSRs)) loci was studied in a sample of 54 plants representing a natural population of wild barley, Hordeum spontaneum, at the Neve Yaar microsite in Israel. Wild barley at the microsite was organized in a mosaic pattern over an area of 3180 m2 in the open Tabor oak forest, which was subdivided into four microniches: (i) sun-rock (11 genotypes), (ii) sun-soil (18 genotypes), (iii) shade-soil (11 genotypes), and (iv) shade-rock (14 genotypes). Fifty-four genotypes were tested for ecological-genetic microniche correlates. Analysis of 36 loci showed that allele distributions at SSR loci were nonrandom but structured by ecological stresses (climatic and edaphic). Sixteen (45.7%) of 35 polymorphic loci varied significantly (p < 0.05) in allele frequencies among the microniches. Significant genetic divergence and diversity were found among the four subpopulations. The soil and shade subpopulations showed higher genetic diversities at SSR loci than the rock and sun subpopulations, and the lowest genetic diversity was observed in the sun-rock subpopulation, in contrast with the previous allozyme and RAPD studies. On average, of 36 loci, 88.75% of the total genetic diversity exists within the four microniches, while 11.25% exists between the microniches. In a permutation test, G(ST) was lower for 4999 out of 5000 randomized data sets (p < 0.001) when compared with real data (0.1125). The highest genetic distance was between shade-soil and sun-rock (D = 0.222). Our results suggest that diversifying natural selection may act upon some regulatory regions, resulting in adaptive SSR divergence. Fixation of some loci (GMS61, GMS1, and EBMAC824) at a specific microniche seems to suggest directional selection. The pattern of other SSR loci suggests the operation of balancing selection. SSRs may be either direct targets of selection or markers of selected haplotypes (selective sweep).     

Genetic contribution of the BAT2 gene microsatellite polymorphism to the age-at-onset of insulin-dependent diabetes mellitus

The BAT2 gene lies within the class III region of the major histocompatibility complex. We investigated the frequency of the BAT2 microsatellite alleles (BAT2) in 74 young-onset insulin-dependent diabetes mellitus (IDDM) patients, 51 adult-onset IDDM patients, and 85 normal control subjects, and assessed the associations among these BAT2 alleles, TNFa microsatellite alleles (TNFa), and HLA-DRB1 alleles. The frequency of the BAT2.9 allele was significantly increased in the young-onset IDDM patients (12.8 vs 4.1%, Pc=0.04896), whereas the frequency of BAT2.12 allele was significantly decreased in young-onset IDDM patients (0.0 vs 11.8%, Pc=0.00002) compared with control subjects. The BAT2.9 allele was strongly associated with TNFa9 in the young-onset IDDM patients, although no association was found between the BAT2.9 and HLA-DRB1 alleles. The BAT2.12 allele was strongly associated with TNFa13, and with DRB1*1502 in control subjects. These results suggest that the BAT2 microsatellite polymorphism is associated with the age-at-onset of IDDM and possibly with the inflammatory process of pancreatic beta-cell destruction during the development of IDDM. However, this association is not independent of TNFa polymorphisms.     

Prevalence of alleles of polymorphic variants Leu33Pro and Leu66Arg gene ITGB3 among inhabitants of Siberia

The frequency of the polymorphic variant T196C (Leu33Pro, rs5918) of ITGB3 gene was studied in several groups of inhabitants of Siberia, including women with reproductive disorders (n = 186), patients with acute coronary syndrome (n = 330), and population control (n = 858). The frequency of the rare PLA2 allele among residents of Tomsk and Kemerovo was 14.7% and 15.0% respectively. There were no differences in the allele and genotype frequencies of polymorphic variant between patients with acute coronary syndrome and the control group (p = 0.925, p = 0.622). The highest frequency of abnormal PLA2 allele (22.1%) and the PLA2/PLA2 genotype (8.8%) was observed among women who had miscarried, which was significantly different from the frequency of this allele and genotype in the control group (14.7%, p = 0.017; 2.1%, p = 0.0009). Sequencing showed that all samples with the nonspecific band had the polymorphic rs5918 variant and rs36080296 mutations (T216G, Leu66Arg). The frequency of the rs36080296 mutation among the residents of Siberia was 0.51%. Among the women with reproductive disorders, the frequency of rs36080296 was 2.7%, while in the group who suffered from miscarriages, it was 4.4%; this was different from the frequency in the control group (0.08%, p = 0.2 × 10^?6). The accumulation of mutations was also observed among men with acute coronary syndrome (0.6%), but the differences from the control group (0%) had no statistical significance. Thus, the rs36080296 mutation may be a factor in predisposition to miscarriage, especially in combination with the PLAII allele. In addition, the rs36080296 variant among men may be associated with acute cor onary syndrome, which requires further study.     

Salinity-related fitness differences amongst GPI genotypes in the mosquitofish Gambusia holbrooki (Poeciliidae: Teleostei)

Salinity-induced mortality was examined in the mosquitofish Gambusia holbrooki to determine if natural selection associated with the tidal inundation of lower reach populations could potentially maintain glucose-6-phosphate isomerase ( GPI -2; E.C. 5.3.1.9) allele frequency variation observed at field sites. In vitro experiments established if survival was independent of GPI -2 genotype, and/or standard body length (S.L.). Bioassay results at 17%₀ were consistent with lower survival of GPI -2*88/88 homozygote genotypes, GPI -2*100/100 genotypes in juvenile size classes, and greater survival of GPI -2*109/100 genotypes; 100% mortality was observed at salinities of 30%₀. In the early stages of the 30%₀ bioassay, juvenile fish carrying each GPI -2 allele suffered similar, high rates of mortality. Following 19 weeks exposure to 4–8%₀ NaCl the frequency of GPI -2*88 alleles decreased in adult G. holbrooki (> 17 mm SL). Salinity-induced mortality was found to be a selective influence capable of creating and maintaining GPI -2 allele frequency differences among G. holbrooki subpopulations, and/or between sex/size cohorts within subpopulations, but only at intermediate salinities. Whether saltwater inundation at field sites maintains inter-population diversity and produces local adaptation will be determined by the age structure of the population during periods of exposure, fluctuations in salinity as determined by the relationship between rainfall and tidal regime, and the level of immigration from non-affected sites.     

Analysis of frequency of DR3 allele in rapidly evolutive forms of Crohn disease in adults; comparison with the occurrence of this allele in slowly evolutive forms and in the normal population]

This communication reports 1. the frequency of the DR3 allele among 86 patients exhibiting various evolutive courses of Crohn's disease (CD), diagnosed in the same hospital in Alsace, France, hospitalized at least once between 1964 and 1986 and followed for at least 1 year, 2. the frequency of the DR3 allele among a control population in the same area: 126 volunteers donors of bone marrow. The definition of the evolutive course was similar to the one published by Binder et al.: slow course (including: intermittent: "occurrence of symptom-free period(s) of at least one month's duration excluding period where the patient was in steroid treatment"; and inactive: "completely free of bowel symptoms during the year") as opposed to continuous evolution: "without symptom-free periods". The DR3 allele determination was established by classical serologic analysis. 26 patients were found with the DR3 allele; 14 belonged to the slow course group, 12 to the continuous evolution group; 60 patients did not exhibit the DR3 allele: 50 in the slow course group, 10 in the continuous evolution group. chi 2 = 8.28; p = 0.004. Therefore the frequency of the DR3 allele was very significantly higher in the group with the continuous course (55%) than in the slow course group (22%). Similarly the frequency of the DR3 allele in the group with the continuous course (12/22: 55%) was significantly higher than in the group of control subjects (34/126: 28%) chi 2 = 6.64; p = 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inter and intra subpopulation genetic variability of roe deer (Capreolus capreolus L.) assessed by I and II class genetic markers

The material was collected in three regions of Poland and consisted of 105 randomly chosen individuals killed during hunts (49 males, 56 females), out of which 51 were from Wielkopolska, 22 from Podkarpacie and 32 from Warmia. From each animal a blood sample was taken from the chest, stored in a probe with K2EDTA and frozen. The serum was used to establish the genotype for transferin and albumin whereas the samples with erythrocytes provided information on hemoglobin genotype. DNA was isolated from samples from each individual. Characteristics of eight (from among twelve studied) microsatellite loci and genetic distances were estimated by the use of standard computer package programs. Generally, monomorphism in blood proteins was registered. For the microsatellite loci the number of alleles ranged from 3 in the RT27-6-Fa locus (effectively two as the third allele was present only in two subpopulations with a very low frequency) to 10 in RT1-VI. Five loci showed heterozygosity of 0.5 or above which suggests their usefulness in parentage control. Considerable genetic distances (corresponding to geographical mileages) between the subpopulations were observed based on microsatellite markers.     

The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus

The dopamine D4 receptor gene (DRD4) has an expressed polymorphism in the third exon that may have functional relevance. The polymorphism exists at two levels. At the higher level there is an imperfect tandem repeat of 48 base pairs (bp) coding for 16 amino acids; alleles have been identified with 2 (32 amino acids) to 10 (160 amino acids) repeats. The imperfect nature of the repeats is responsible for a more subtle level of variation since alleles with the same number of repeats can differ in the exact sequences or in the order of the variants of the 48-bp unit. We have undertaken a global survey of this expressed polymorphism as one approach to understanding the evolutionary significance and origins of the polymorphism as well as understanding what selective forces, if any, may be operating at this locus. As the first step, we have determined the repeat number genotype of the DRD4 repeat polymorphism in 1,327 individuals from 36 different populations. The allele frequencies differ considerably among the different populations. The 4-repeat allele was the most prevalent (global mean allele frequency = 64.3%) and appeared in every population with a frequency ranging from 0.16 to 0.96. The 7-repeat allele was the second most common (global mean = 20.6%), appearing quite frequently in the Americas (mean frequency = 48.3%) but only occasionally in East and South Asia (mean frequency = 1.9%). The 2-repeat allele was the third most common (global mean frequency = 8.2%) and was quite frequent in East and South Asia (mean frequency = 18.1%) while uncommon in the Americas (mean frequency = 2.9%) and Africa (mean frequency = 1.7%). The universality of the polymorphism with only three common repeat-number alleles (4, 7, and 2) indicates that the polymorphism is ancient and arose before the global dispersion of modern humans. The diversity of actual allele frequencies for this expressed polymorphism among different populations emphasizes the importance of population considerations in the design and interpretation of any association studies carried out with this polymorphism. Received: 18 July 1995 / Revised: 18 December 1995     

Testing for association in the presence of population stratification: a simulation study comparing the S-TDT, STRAT and the GC

A novel approach for association testing in the presence of population stratification has been introduced by Pritchard et al. (2000a) and Pritchard et al. (2000b). The structured association approach is a two-tiered procedure that first estimates the population structure and then tests the null hypothesis H0: 'no association within subpopulations' in the second step. A power comparison of the stratified test for association (STRAT) (Pritchard et al., 2000b) and the Transmission-Disequilibrium-Test (TDT) (Spielman and Ewens, 1993a) in a simulation framework showed superiority of STRAT if allele frequencies or associations between allele and disease differ strongly in subpopulations. In more homogeneous situations, the TDT had greater power than STRAT. However, the TDT, based on family trios,that uses population controls, needs 50% more genotyping compared to STRAT. The Sib-Transmission-Disequilibrium-Test (S-TDT) needs the same amount of genotyping since it relays in its minimal configuration on pairs of siblings. This raises the question how the S-TDT (Spielman and Ewens, 1998a) performs compared to the population based methods STRAT and Genomic Controls (GC). In this paper, we present a simulation study accounting for two different models of population stratification in different settings of allele frequencies and under different risk models. The results showed that under a discrete as well as under an admixed population model, STRAT strongly outperformed the S-TDT and the GC when different alleles were associated in different subpopulations. In contrast, the S-TDT had greater power than STRAT when the same allele was associated in both subpopulations. Here, the GC was sometimes even more powerful than the S-TDT, depending on the population model and the allele frequency differences. A general recommendation for the use of one of the tests can therefore not be given.     

Alcohol dehydrogenases ADH1B and ADH7 gene polymorphism in Russian population from the Siberian region

The Allele and genotype didtributions of the two alcohol dehydrogenase genes ADH1B (polymorphism A/G in exon 3, detected with restrictase MslI) and ADH7 (polymorphism G/C in intron 5, detected with restrictase StyI) was studied in three Russian populations from the Siberian region. The absence of interpopulation and intersexual differences in the allele frequency was determined. The allele ADH1B*G (+MslI, A2) was found in low frequency (3.6-7.5%), the mutant allele ADH7 (-StyI, B2) frequency in total population (n = 339) was 46.02%. The genotype distributions of the ADH1B and ADH7 in these populations were agreed with the Hardy-Weinberg equilibrium and linkage equilibrium. Increased frequency of ADH7 B2 allele was revealed in elder group (after 40 years) in the total sample and in the Tomsk city inhabitants (n = 113) on 11% (P = 0.001) and 9% (P = 0.017) accordingly. ADH7 and ADH1B genes polymorpisms did not show association with antioxidant activity, which was determined from the blood plasma ability to reduce the yield of products interacting with thiobarbituric acid in the lecitin-Fe2+ ions model system. The statistically significant decrease of serum very low density lipoproteins (LPVLD) level (on 9.95%, P = 0.045) and close to statistically significant decrease systolic pressure (on 6.80%, P = 0.068) and serum triglycerides level (on 6.16 of %, P = 0.058) were revealed among the A2 allele ADH1B gene carriers in Tomsk population.     

Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test

The transmission/disequilibrium test (TDT), a family-based test of linkage and association, is a popular and intuitive statistical test for studies of complex inheritance, as it is nonparametric and robust to population stratification. We carried out a literature search and located 79 significant TDT-derived associations between a microsatellite marker allele and a disease. Among these, there were 31 (39%) in which the most common allele was found to exhibit distorted transmission to affected offspring, implying that the allele may be associated with either susceptibility to or protection from a disease. In 27 of these 31 studies (87%), the most common allele appeared to be overtransmitted to affected offspring (a risk factor), and, in the remaining 4 studies, the most common allele appeared to be undertransmitted (a protective factor). In a second literature search, we identified 92 case-control studies in which a microsatellite marker allele was found to have significantly different frequencies in case and control groups. Of these, there were 37 instances (40%) in which the most common allele was involved. In 12 of these 37 studies (32%), the most common allele was enriched in cases relative to controls (a risk factor), and, in the remaining 25 studies, the most common allele was enriched in controls (a protective factor). Thus, the most common allele appears to be a risk factor when identified through the TDT, and it appears to be protective when identified through case-control analysis. To understand this phenomenon, we incorporated an error model into the calculation of the TDT statistic. We show that undetected genotyping error can cause apparent transmission distortion at markers with alleles of unequal frequency. We demonstrate that this distortion is in the direction of overtransmission for common alleles. Therefore, we conclude that undetected genotyping errors may be contributing to an inflated false-positive rate among reported TDT-derived associations and that genotyping fidelity must be increased.