Frequency and distribution of rare electrophoretic mobility variants in a population of human newborns in Ann Arbor, Michigan

We have summarized the frequency and distribution of the rare variants encountered during the screening of 258 815 allele products, the products of 51 different loci, in 3242 predominantly Caucasian (88 %) newborns. Seventy-nine different rare variants, representing 187 occurrences, were identified. Almost 60 % (46 of 79) of the rare variants occurred as singletons while another 20 % were seen in two unrelated individuals. No rare variants were detected at 18 loci while no variants, either rare or polymorphic, were detected at 14 loci. More rare variants were identified at loci that were classified as polymorphic and also at loci where the gene products exist as a monomer. A positive relationship was observed between variant frequency, either classes or copies, and subunit molecular mass.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65173/1/j.1469-1809.1987.tb01065.x.pd

Characterization of a series of electrophoretic and enzyme activity variants of human glucose-phosphate isomerase

A total of 3438 cord blood samples were screened for variants of erythrocyte glucose-phosphate isomerase. The five different electrophoretic, three activity/deficiency, and one thermostability variants distributed among 27 unrelated Caucasian families of that population, plus two electrophoretic variants previously described from three Amerindian tribes were subsequently examined for cryptic variation using activity and thermostability criteria. Although thermostability differences were observed between electrophoretic variants, no microheterogeneity within any one class of variant was detected.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47616/1/439_2004_Article_BF00273834.pd

Studies of the purine analog associated modulation of human erythrocyte acid phosphatase activity

The activity of the human erythrocyte acid phosphatase is modulated by a series of structural analogs of purine. The unsubstituted purine base does not affect the enzyme activity. Addition of a substituent at the number six position usually generates an analog which activates the enzyme while similar substitutions at the two position usually generate an inhibitor. Pyrimidines are generally ineffective as modulators while several modifications of the imidazole ring of the purine analogs do not abolish the modulator activity of the purine analog. The level of response to all active analogs is isozyme specific. Differences in apparent relative affinities among the modulators are noted. The modulators with a positive effect on enzyme activity, are effective in the presence of methanol which is more effective than H 2 0 as a phosphate acceptor. These analogs act by enhancing the rate of transfer of phosphate to H 2 O, while decreasing the rate of transfer to methanol. The results suggest that the purine analogs may act by altering the rate of hydrolysis of the phosphoenzyme intermediate by H 2 0 or may change the rate-limiting step in the catalytic mechanism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45350/1/11010_2004_Article_BF00220780.pd

The Effectiveness of Co-Determination Laws in Cooperative and Adversarial Employment Relations: When Does Regulation Have Bite?

The German Codetermination Law grants workers of establishments with 200 or more employees the right to have a works councillor who is fully exempted from his or her regular job duties while still paid a regular salary. This article analyses theoretically and empirically how this de jure right to exemption translates into de facto practice, and explicitly takes into account the nature of the employment relations participation regime. It is found that the right of exemption has no effect in cooperative employment relations because exemptions are granted even in the absence of legal rights, but does make a difference in adversarial relations when exemptions are only granted above the threshold where legal rights force employers to do so, i.e. legal rights do make a decisive difference in exactly those situations where the legislators’ intent would not be realized without the right to legal enforcemen

Exploration of methods to identify polymorphisms associated with variation in DNA repair capacity phenotypes

Elucidating the relationship between polymorphic sequences and risk of common disease is a challenge. For example, although it is clear that variation in DNA repair genes is associated with familial cancer, aging and neurological disease, progress toward identifying polymorphisms associated with elevated risk of sporadic disease has been slow. This is partly due to the complexity of the genetic variation, the existence of large numbers of mostly low frequency variants and the contribution of many genes to variation in susceptibility. There has been limited development of methods to find associations between genotypes having many polymorphisms and pathway function or health outcome. We have explored several statistical methods for identifying polymorphisms associated with variation in DNA repair phenotypes. The model system used was 80 cell lines that had been resequenced to identify variation; 191 single nucleotide substitution polymorphisms (SNPs) are included, of which 172 are in 31 base excision repair pathway genes, 19 in 5 anti-oxidation genes, and DNA repair phenotypes based on single strand breaks measured by the alkaline Comet assay. Univariate analyses were of limited value in identifying SNPs associated with phenotype variation. Of the multivariable model selection methods tested: the easiest that provided reduced error of prediction of phenotype was simple counting of the variant alleles predicted to encode proteins with reduced activity, which led to a genotype including 52 SNPs; the best and most parsimonious model was achieved using a two-step analysis without regard to potential functional relevance: first SNPs were ranked by importance determined by Random Forests Regression (RFR), followed by cross-validation in a second round of RFR modeling that included ever more SNPs in declining order of importance. With this approach 6 SNPs were found to minimize prediction error. The results should encourage research into utilization of multivariate analytical methods for epidemiological studies of the association of genetic variation in complex genotypes with risk of common diseases

Functional hemizygosity in the human genome: direct estimate from twelve erythrocyte enzyme loci

Cord blood samples from 2020 unrelated newborns were screened for levels of enzyme activity for twelve enzymes. The level of enzymatic activity for 100 determinations were consistent with the existence of an enzyme-deficiency allele. The frequency of deficiency alleles in the Black population (0.0071) was four times higher (after removal of the G6PD * A - variant) than in the Caucasian sample (0.0016). These frequencies are approximately double the frequency of rare electrophoretic mobility variants at similar loci in the same population. Given the number of functionally important loci in the human genome, these enzyme deficiency variants could constitute a significant health burden.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47620/1/439_2004_Article_BF00284477.pd

Analysis of the XRCCI gene as a modifier of the cerebral response in ischemic stroke

Background: Although there have been studies of the genetic risk factors in the development of stroke, there have been few investigations of role of genes in the cerebral response to ischemia. The brain responds to ischemia in a series of reactions that ultimately influence the volume of a stroke that, in general, correlates with disability. We hypothesize that polymorphisms in genes encoding proteins involved in these reactions could act as modifiers of this response and impact stroke volume. One of the pathways participating in the cerebral ischemic response involves reactive oxygen species which can cause oxidative damage to nucleic acids. DNA repair mechanisms are in place to protect against such damage and imply a role for DNA repair genes in the response of the brain to ischemia and are potential candidate genes for further investigation. Methods: We studied two common polymorphisms in the DNA repair gene, XRCC1, C26304T and G28152A, in 134 well characterized patients with non lacunar ischemic strokes. We also performed a case control association study with 113 control patients to assess whether these variants represent risk factors in the development of ischemic stroke. Results: Independent of etiology, the T allele of the C26304T polymorphism is significantly associated with larger stroke volumes (T-test analysis, p < 0.044; multivariate regression analysis, beta = 0.23, p < 0.008). In the case control association study, we found that neither of these polymorphisms represented a risk factor for the development of stroke. Conclusion: Our study suggests a major gene effect of the T allele of the C26304T polymorphism modulating the cerebral response to ischemia in non lacunar ischemic stroke

Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes

BACKGROUND: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFß1, IGFBP3) were evaluated. METHODS: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. RESULTS: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3–3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1–3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6–29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFß1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. CONCLUSION: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted