Genetic Marker Systems Research Articles

Estimation of gene/haplotype frequencies in genetic marker systems based on phenotype data

Two equivalent methods (gene counting and maximum likelihood) for estimating gene frequencies in a general genetic marker system based on observed phenotype data are derived. Under the maximum likelihood approach, an expression is given for the estimated covariance matrix from which estimated standard errors of the estimators can be found. In addition, consideration is given to the problem of estimating gene frequencies when there are available several independent population data sets.

AIDS: no association with the genetic systems GC (D-binding protein), ORM (orosomucoid = alpha-1-acid glycoprotein), and A2HS (alpha-2-HS-glycoprotein).

In a sample of 97 HIV-1 seropositive persons which comprised 34 patients with AIDS, 30 patients with persistent generalized lymphadenopathy or with AIDS related complex and 33 persons who were without symptoms and called "healthy", three genetic marker systems were examined: 1) GC, the group-specific component of serum which is identical with the vitamin D binding protein (DBP) of serum, 2) ORM, the acute phase protein orosomucoid = alpha-1-acid glycoprotein of serum, and 3) A2HS, the alpha-2-AS glycoprotein of serum. The distribution of the genotypes and of the alleles in the sample of AIDS patients and of HIV-1/positive persons was not different from the distribution in control groups. An association between susceptibility and/or resistance for AIDS and these genetic marker systems was not observed.

The Gm system. Anti-Gm's: characteristics in rheumatoid arthritis; experimental induction without resort to allotype; frequent occurrence in mononucleosis.

Gm system: Some RFs specifically detect Mendelian markers of human Ig, originally proving that Ig production is gene controlled. The genetic marker systems of human Ig with 17 Gm, 2 Am, 3 Km and 1 Em markers are briefly described. Examples of the usefulness of the Gm system in medicine, immunology and molecular biology are mentioned. 1. Some RFs have been essential tools in elucidating genetic control mechanisms in Ig production. 2. Knowledge of the Gm system is extensive. Anti-Gm's: High-titered anti-Gm's are common in R.A. The anti-allotypes in R.A. are markedly restricted as to their specificity. They are usually not directed against the individuals own Gm markers. Anti-human-immunoglobulins were observed in 12 of 18 sera from patients with mononucleosis. The majority of these anti-immunoglobulins were inhibitable by native human Ig and showed restricted specificity. 1. There is a strong stimulus for production of particular anti-Gm's in a majority of R.A. cases. 2. Notions of an autoimmune origin for many anti-Gm's in R.A. are not in obvious agreement with experimental observations. 3. Anti-human-Ig's with restricted specificity are commonly induced in mononucleosis.

Electrophoresis Reliability: I. The Contaminant Issue

The effects of the common contaminants--soil, oil, gasoline, salt, acid, base, bleach, and detergent--on various forensically used genetic marker systems were studied. The predicted effects of the various contaminants on the proteins and the electrophoretic separations agreed with the observed results. A contaminant that affected protein conformation also adversely affected the integrity of the electrophoretic system, thus signalling an anomaly. It also was pointed out that the ideal control study for the effects of contaminants on genetic markers in evidentiary material is often provided to forensic scientists--that is victim's blood on victim's clothing and other substrata. The data presented in this paper support the validity and reliability of electrophoretic analyses of evidentiary material with respect to the contaminant issue.

Major genes of eye color and hair color linked to LU and SE.

Eye color and hair color were studied in a large Danish family material, tested earlier for a comprehensive set of genetic marker systems. We found strong evidence for linkage of "green eye color" or GEY to the Lutheran-Secretor systems (combined lod score 9.19). This would appear to identify a major gene with influence towards "green eye color". We also found evidence for linkage of GEY to "brown hair color" or BRHC (lod score 5.06), which would appear to identify a second major gene influence in the same region of chromosome 19. Concerning the obvious association in the general population between eye color and hair color which could imitate linkage if it were reflected within sibships, we did not recognize any such intrafamilial association; in the pooled informative sibships GEY and BRHC were independently distributed (as were LU-SE and GEY).

Hereditary hemorrhagic telangiectasy (HHT) and HLA.

Linkage between HHT and 10 genetic marker systems was investigated in a family with 7 affected members. The analysis supports the previously suggested linkage between HLA and HHT (theta = .17).

Familial hypokalemic periodic paralysis. 50-year follow-up of a large family.

A large family with hypokalemic periodic paralysis was reexamined after 50 years. Two new cases were found in the third generation and 12 in the fourth generation. This family now includes 28 affected patients in four generations. The reexamination ascertained the presence of permanent muscle weakness (PMW) in all investigated affected sibs. This fact, and the fact that indications of the presence of PMW without paralytic attacks were found in only one subject, is strong evidence that both are manifestations of the same more or less fully penetrant dominant gene. A linkage study in this family could not localize the gene on the human genome, but close linkage with 25 genetic marker systems could be excluded.

Transferrin C subtypes and occupational photodermatosis of the face.

In a factory in northern Sweden where 120 workers were uniformly exposed to photoactive substances 73 developed occupational facial eczema while 47 showed no reaction. The workers were examined with respect to 16 genetic marker systems: HLA, blood groups (ABO, Rh, MNSs, P, K, Le and Fy) and serum groups (Hp, Tf, Gc, Pi, Bf, C3, C4 and C6). Between reactors and nonreactors the following differences were found: (1) a significant decrease (p less than 0.05) of HLA A11 among the reactors; (2) a significant increase (p less than 0.05) of the C3 FS type among the reactors; (3) a highly significant increase (p less than 0.001) of the transferrin C2 gene and of the C2 variant among the reactors. The association with Tf C2 remained significant also after correction for number of significance tests. Since transferrin (iron) is known to catalyze the formation of hydroxyl radicals we hypothesize that the Tf C2 variant is more efficient in promoting radical formation and thereby cell damage. Other results supporting the notion that transferrin C2 may be associated with an increased susceptibility to toxic damage are discussed.

Review of isoelectric focusing for Gc, PGM1, Tf, and Pi subtypes: population distributions.

Isoelectric focusing (IEF) as a method for differentiating macromolecules with minor differences in isoelectric points has demonstrated an increase in the degree of genetic polymorphisms of the blood. Studies over the last 5 to 6 years have shown that genetic marker systems such as transferrin (TF), phosphoglucomutase (PGM1), the vitamin D-binding globulin (GC), and A1 antitrypsin (PI) are a great deal more polymorphic than observed using conventional electrophoresis. Additional genetic variants have been detected or further defined in such systems as esterase D (ESD) and hemoglobin (HB) to name a few. The increased heterozygosity levels of these genetic marker systems identified by IEF have added to their value in forensic medicine and resulted in further resolution of racial and population affinities. IEF should prove to be a valuable anthropological tool for measuring population structure and genetic distances.

The Distribution of the Paternity Index as a Basis for Evaluation of Sequential Testing in Paternity Analysis

Several procedures for evaluation of paternity testing data have been suggested in the literature, the majority of them being based on the paternity index statistic (L) or some transform of it. A major problem has been that the true distribution of the paternity index has not been known, making it difficult to perform quantitative evaluations of different procedures. We present an algorithm for computation of the distribution of the paternity index within the limits of a completely controlled amount of approximation. Using this algorithm we evaluate the power and the rate of erroneous classifications of a standard routine test based on a fixed number of genetic marker systems. The efficiency of this standard test procedure is compared to a stepwise (sequential) procedure where in each step one or several marker systems are scored for the mother-child-putative father trio. We suggest that a sequential strategy for testing may be more efficient than one that is based on a fixed number of systems. A sequential procedure can provide information about the accused man's state of paternity in a considerably larger fraction of cases without a substantial increase of the frequency of incorrect classifications. In addition, the cost measured as the average number of marker systems that has to be tested for each trio may be lower in the case of sequential testing than with a fixed number of systems.

A family study of HLA antigens and other genetic markers in schizophrenia.

HLA antigens and 19 other genetic marker systems were studied in 12 families containing 2 or more members diagnosed as schizophrenic. In contrast with previous reports we could exclude linkage between the disorder and HLA, and we found no evidence of linkage with Gm or Gc. The disagreement between our results and those of a previous study, which suggested linkage between HLA and schizophrenia, could not be explained on the basis of genetic heterogeneity within the disorder. The problems of performing a linkage study in the face of diagnostic uncertainty and an unknown mode of inheritance of the main trait are discussed, and the measures taken in attempts to overcome these difficulties are described. Despite present drawbacks, genetic marker studies hold future promise as a means of detecting major gene effects in schizophrenia and other familial psychiatric disorders.

Absence of close linkage between Hereditary spherocytosis (SPH) and 24 genetic marker systems including HLA and GM.

A total of 250 individuals belonging to 19 different families, identified through established propositi were simultaneously screened for hereditary spherocytosis (SPH), using stringent criteria, and 27 well-known polymorphic genetic marker systems. The segregation analysis indicated that the pattern of inheritance of SPH in these families, being autosomal and dominant, had a 100% penetrance. A statistical analysis, using the LIPED computer program of Ott (1974), revealed the absence of close linkage between SPH and ABO, ACP1, ADA, AK1, C3, DIA2, ESD, FY, GC, GLO1, GM, GPT1, HLA, HPA, JK, K, KM, MNS, P, PGD, PGM1, PGP, PI, and RH. Since an earlier study by other investigators had convincingly suggested a linkage between SPH and GM, we subjected the data to further analysis and found no significant heterogeneity in our recombination values of linkage between SPH and GM, or any of the other informative loci.

The parameters for quantitative analysis of mutation rates with cultured mammalian somatic cells

In their classic paper which demonstrated the preadaptive origin of phage resistance in bacteria, Luria and Delbriick (1943) proposed the use of the fluctuation test to estimate mutation rates in a bacterial population. Subsequently, a number of investigators have examined this problem from various angles, including formal derivations (Newcombe, 1948), mathematical models (Stocker, 1949), mutant distribution (Lea and Coulson, 1950) and statistical theories (Armitage, 1952, 1953). The study in this problem has been continued until recently (Kondo, 1972; Gilbert, 1980), all dealing with the formulae and methods for estimating mutation rates in bacteria. Since the initial demonstration of experimental mutagenesis in cultured mammalian cells (Chu and Malling, 1968; Kao and Puck, 1968), fluctuation analysis has been applied for quantitative estimation of mutation rates (Shapiro et al., 1972; Morrow, 1975). There has nevertheless been a great disparity among published rate estimates from experiments with a variety of cells and genetic marker systems; using the same genetic marker in the same cell types, differences in mutation rates have even been found in different experiments by the same laboratory. For instance, Albertini and DeMars (1973) estimated the spontaneous mutation rate to 8-azaguanine resistance in human diploid fibroblasts and obtained values in 5 Expts. varying by a factor of 14 (0.788 x 10 6 to 1.115 x 10 -5 per cell per generation. There are at least 3 sources of error that may be responsible for such differences. The most obvious would be the sampling error, but it is too big a range of values to be the sole source. The second source of error may be biological, which has been described in some detail by Abbondandolo (1977). The third type of error may originate from differences in experimental design. There are at least 5 different methods for the estimation of mutation rates, namely, the mean, the upper quartile, the median, the Po and the maximum likelihood methods (Luria and Delbr~ick, 1943; Newcombe, 1948; Lea and Coulson, 1950; Armitage, 1952; 1953; Kondo,

No evidence for linkage between hla and maturity onset type of diabetes in young people

Studies with 20 different genetic marker systems were performed in a large kindred including 18 members affected with maturity onset type of diabetes of young people. Linkage closer than 0.1⩽θ could be excluded for ABO and Gm, and linkage closer than 0.05⩽θ for HLA GLO, and haptoglobin. No significant positive lod scores were found.

Linking a Bloodstain to a Missing Person by Genetic Inheritance

The use of the principles of genetic inheritance to link a bloodstain to a missing victim is discussed. Genetic marker typing can determine whether the parents of the missing victim are possible parents of the bloodstain source. Given a parental inclusion, it is possible to calculate the probability that a randomly selected couple would possess the necessary genetic combinations to be the parents of the person who bled. The applications of this concept using several genetic marker systems are examined. General formulas have been developed for the probability calculation using phenotype distribution frequencies and gene frequencies. This approach was applied to a homicide case in which it was shown that the victim's parents were among only 0.8% of couples from the general population who would be able to bequeath the genetic marker types found in the bloodstain. This evidence was helpful in producing a conviction of first degree murder.

Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan-VI. A search for genotype by environment interaction

We have examined 12 unlinked polymorphic genetic marker systems and found 6 which each identified small but statistically significant differences in normal serum cholesterol levels which did not change significantly with age. The effects associated with 4 of the 6-ABO haptoglobin, Gm and secretor—were consistent in males and females and combined additively to define effects which were also homogeneous over age. There was a marker phenotype by age interaction effect on cholesterol variance in females but not in males. This study supports the hypothesis that a number of polymorphic genes, each with a small additive effect on cholesterol level, play an important role in determining cholesterol variability.

Frequencies of salivary genetic marker systems in Caucasians with an emphasis on Pm and Ph systems

Salivary genetic marker systems, especially the Pm and Ph systems, were studied in Caucasians. The gene frequencies obtained were, Pm + = 0.14 and Pm − = 0.86. A variant polymorphic protein (Ph) present in the Japanses population was not observed in Caucasians.

Exclusion of paternity without testing the mother.

On the basis of the existence of incompatible phenotypes between the child and the alleged father, exclusion of paternity can be obtained even when the mother is not available for testing. Incompatible phenotypes in each genetic marker system of common erythrocyte antigens and enzymes, serum proteins, and major histocompatibility antigens are compiled. The efficiencies of each system and groups of systems in the exclusion of paternity are estimated; the cumulative chance is about 88% if all the common genetic marker systems are utilized.

Frequency Distribution of Genetic Markers in Guernsey Cattle1,2

Ten polymorphic systems of blood antigens and blood proteins were analyzed in 6,802 Guernsey cows from 77 herds and 11 states. The numbers of alleles identified with frequencies >1% in the A, B, C, F, J, L, M, S, and Z blood antigen systems and the alkaline phosphatase system were 3, 17, 11, 2, 2, 2, 1, 3, 2, and 2. Gene frequencies were determined by maximum likelihood, allocation, and square root methods for the dominant systems and by the gene counting method for the codominant system. Distributions varied greatly in the different systems. Comparisons among these and other blood and milk genetic marker systems revealed lack of independence of J and alkaline phosphatase phenotypes, J and milk protein β-lactoglobulin phenotypes, and of combined phenotypes of the three systems. More cows than expected were J-negative when alkaline phosphatase A was present or when β-lactoglobulin B was present. Phenotypes of blood antigen system A and hemoglobin were also different from independent assortment. More hemoglobin B cows had blood antigen system A phenotype A than the other phenotypes. The blood antigen locus F had more heterozygous cows than were expected for Hardy-Weinberg equilibrium.

Natural selection and the origin and maintenance of standard genetic marker systems

AbstractNatural selection has always been assumed to be the major force of evolution, but its presence has been difficult to demonstrate. A review of the evidence for selective differences among genotypes for most human genetic polymorphisms indicates there is little of a direct nature. Indirect theoretical evidence, however, seems to support a major role for natural selection, and it does not seem to support the hypothesis that most amino acid substitutions within the human species are neutral. Among small isolates, most of the gene frequency differences are most likely due to genetic drift or the founder effect, and the principal counterbalancing force is gene flow or migration. But genetic differences among the major human subdivisions do not seem to be due to the same interacting forces. One reason for the inability to detect selection has been an oversimplified view of its operation, which assigns genotypes a constant fitness in every generation. Many recent theoretical developments of more complicated kinds of selection may lead to a resolution of the problem and suggest better interpretations of the enormous amount of data on human genetic variation that is rapidly accumulating.