Genetic-epidemiologic study of adenoma and cancer of the large intestine]

A clinical/genealogical study of colorectal adenomas (CRA) and cancer (CRC), and multiple primary malignant tumors (MPMT) was performed. The CRA prevalence in the population was 4.7 +/- 1.4% (single CRA--6.3% and multiple CRA--3.0%). The frequencies of malignant adenomas, 0.7% CRC, and MPMT were 0.7, 0.17 +/- 0.07%, and 0.004 +/- 0.003%, respectively. The prevalence of cancer of the female reproductive organs was also estimated (cancer of uterine body, 0.2 +/- 0.1%; cancer of ovaries, 0.08 +/- 0.1%; cancer of uterine cervix, 0.55 +/- 0.1%; cancer of mammary gland 0.57 +/- 0.1%). The main parameters of the familial inheritance of adenomas, CRC, and MPMT were also studied in general and at various clinical variants of these pathologies. Among the first-degree relatives of patients with solitary and multiple adenomas, the adenoma frequencies were 5.9 +/- 0.6 and 3.7 +/- 0.5%, respectively. The CRC frequency among the first-degree relatives of patients with adenoma was 3.0 +/- 0.6% and the frequency of MPMT was 5.8 +/- 0.6%. On the basis of the data obtained on frequencies of malignant tumors in various groups of relatives, the following conclusions were made: (1) in families of each proband group, specific pathology was accumulated; (2) the familial frequency of malignant tumors increased with an increase in proliferative processes and the severity of a pathology in probands.     

Split-hand/foot malformation - molecular cause and implications in genetic counseling

Split-hand/foot malformation (SHFM) is a congenital limb defect affecting predominantly the central rays of the autopod and occurs either as an isolated trait or part of a multiple congenital anomaly syndrome. SHFM is usually sporadic, familial forms are uncommon. The condition is clinically and genetically heterogeneous and shows mostly autosomal dominant inheritance with variable expressivity and reduced penetrance. To date, seven chromosomal loci associated with isolated SHFM have been described, i.e., SHFM1 to 6 and SHFM/SHFLD. The autosomal dominant mode of inheritance is typical for SHFM1, SHFM3, SHFM4, SHFM5. Autosomal recessive and X-linked inheritance is very uncommon and have been noted only in a few families. Most of the known SHFM loci are associated with chromosomal rearrangements that involve small deletions or duplications of the human genome. In addition, three genes, i.e., TP63, WNT10B, and DLX5 are known to carry point mutations in patients affected by SHFM. In this review, we focus on the known molecular basis of isolated SHFM. We provide clinical and molecular information about each type of abnormality as well as discuss the underlying pathways and mechanism that contribute to their development. Recent progress in the understanding of SHFM pathogenesis currently allows for the identification of causative genetic changes in about 50 % of the patients affected by this condition. Therefore, we propose a diagnostic flow-chart helpful in the planning of molecular genetic tests aimed at identifying disease causing mutation. Finally, we address the issue of genetic counseling, which can be extremely difficult and challenging especially in sporadic SHFM cases.     

TNF-alpha levels and TNF-alpha gene polymorphism in type I Gaucher disease

The objective of this pilot study was to determine the levels of Tumor Necrosis Factor (TNF)-alpha and TNF-alpha gene polymorphism as a marker of inflammation among patients with type I Gaucher disease as well as to ascertain the relationship between this cytokine and parameters of disease severity and other measures of inflammation. Levels of TNF-alpha and genotyping for the -308 G-->A polymorphism in the promoter of the TNF-alpha gene were performed in 17 patients with type I Gaucher disease. TNF-alpha levels were compared with the promoter gene polymorphism, and with hematological and other clinical parameters of Gaucher disease. Eight patients (47.1%) were homozygotes (A/A) for the TNF-alpha polymorphism, six patients (35.3%) had the wild type (G/G), and three patients (17.6%) were heterozygotes (G/A). A significant correlation was found between serum TNF-alpha levels and TNF-alpha genotypes for homozygotes versus heterozygotes patients (p = 0.02), with patients homozygous for the polymorphism having the lower levels of serum TNF-alpha relative to heterozygotes with the highest levels. No correlation was found between TNF-alpha genotypes and chitotriosidase levels, a putative biochemical marker for Gaucher disease severity. Because a significant correlation was found between homozygosity for a common promoter polymorphism of TNF-alpha and milder expression i.e. non-neuronopathic form, of Gaucher disease (versus the neuronopathic forms), this may be suggestive of an association between genetic variability in TNF-alpha and phenotypic expression in Gaucher disease. Larger studies will be required.     

Influence of mom and dad: quantitative genetic models for maternal effects and genomic imprinting

The expression of an imprinted gene is dependent on the sex of the parent it was inherited from, and as a result reciprocal heterozygotes may display different phenotypes. In contrast, maternal genetic terms arise when the phenotype of an offspring is influenced by the phenotype of its mother beyond the direct inheritance of alleles. Both maternal effects and imprinting may contribute to resemblance between offspring of the same mother. We demonstrate that two standard quantitative genetic models for deriving breeding values, population variances and covariances between relatives, are not equivalent when maternal genetic effects and imprinting are acting. Maternal and imprinting effects introduce both sex-dependent and generation-dependent effects that result in differences in the way additive and dominance effects are defined for the two approaches. We use a simple example to demonstrate that both imprinting and maternal genetic effects add extra terms to covariances between relatives and that model misspecification may over- or underestimate true covariances or lead to extremely variable parameter estimation. Thus, an understanding of various forms of parental effects is essential in correctly estimating quantitative genetic variance components.     

Aberrant DNA Methylation: Implications in Racial Health Disparity

BackgroundIncidence and mortality rates of colorectal carcinoma (CRC) are higher in African Americans (AAs) than in Caucasian Americans (CAs). Deficient micronutrient intake due to dietary restrictions in racial/ethnic populations can alter genetic and molecular profiles leading to dysregulated methylation patterns and the inheritance of somatic to germline mutations.ResultsDNA from the tumor of AA CRC patients, compared to adjacent normal tissues, contained 1,588 hypermethylated and 100 hypomethylated differentially methylated regions (DMRs). Whereas, 109 hypermethylated and 4 hypomethylated DMRs were observed in DNA from the tumor of CA CRC patients; representing a 14.6-fold and 25-fold change, respectively. Specifically; CHL1, 4 anti-inflammatory genes (i.e., NELL1, GDF1, ARHGEF4, and ITGA4), and 7 miRNAs (of which miR-9-3p and miR-124-3p have been implicated in CRC) were hypermethylated in DNA samples from AA patients with CRC. From the same sample set, RNAseq analysis revealed 108 downregulated genes (including 14 ribosomal proteins) and 34 upregulated genes (including POLR2B and CYP1B1 [targets of miR-124-3p]) in AA patients with CRC versus CA patients.ConclusionDNA methylation profile and/or products of its downstream targets could serve as biomarker(s) addressing racial health disparity.     

Diverse morphological types of dormant cells and conditions for their formation in <Emphasis Type="Italic">Azospirillum brasilense</Emphasis>

Differences in generation of dormant forms (DF) were revealed between two strains of non-sporeforming gram-negative bacteria Azospirillum brasilense, Sp7 (non-endophytic) and Sp245 (endophytic strain). In post-stationary ageing bacterial cultures grown in a synthetic medium with a fivefold decreased initial nitrogen content, strain Sp7 formed two types of cyst-like resting cells (CRC). Strain Sp245 did not form such types of DF under the same conditions. CRC of the first type were formed in strain Sp245 only under phosphorus deficiency (C > P). The endophytic strain was also shown to form structurally differentiated cells under complete starvation, i.e. at a transfer of early stationary cultures, grown in the media with C > N unbalance, to saline solution (pH 7.2). These DF had a complex structure similar to that of azotobacter cysts. The CRC, which are generated by both azospirilla strains and belong to distinct morphological types, possessed the following major features: absence of division; specific ultrastructural organization; long-term maintenance of viability (for 4 months and more); higher heat resistance (50–60°C, 10 min) as compared with vegetative cells, i.e. the important criteria for dormant prokaryotic forms. However, CRC of non-endophytic strain Sp7 had higher heat resistance (50, 55, 60°C). The viability maintenance and the portion of heat-resistant cells depended on the conditions of maturation and storage of CRC populations. Long-term storage (for 4 months and more) of azospirilla DF populations at ?20°C was optimal for maintenance of their colony-forming ability (57% of the CFU number in stationary cultures), whereas the largest percentage of heat-resistant cells was in CRC suspensions incubated in a spent culture medium (but not in saline solution) at room temperature. The data on the intraspecies diversity of azospirilla DF demonstrate the relation between certain type DF formation to the type of interaction (non-endophytic or endophytic) with the plant partner and provide more insight into the adaptation mechanisms that ensure the survival of gram-negative non-spore-forming bacteria in nature.     

Cross-species amplification, non-invasive genotyping, and non-Mendelian inheritance of human STRPs in Savannah baboons

Twenty-nine human microsatellite primer pairs were screened for their utility in the cross-species amplification of baboon DNA derived from both blood and feces as part of a larger study to identify paternal half sisters in a population of wild baboons (Papio cynocephalus). Forty-one percent (12/29) of the human primers successfully amplified baboon DNA. Of these 12 primers, six amplified fragments that were both polymorphic and heterozygous (mean number of alleles = 6, mean heterozygosity = 87%) and yielded repeatable results. However, only five of these six simple tandem repeat polymorphisms (STRPs) showed patterns of Mendelian inheritance (i.e., mothers and offspring shared at least one allele at each locus), and were therefore useful for determining relatedness between individuals. Analysis of the sixth primer revealed non-Mendelian inheritance, i.e., three of the six known mother-daughter pairs had no shared alleles. This failure was probably due to non-specific fragment amplification, and may have resulted from a different STRP locus being amplified in mother and daughter. This finding highlights the importance of sampling DNA from known parent-offspring pairs when screening microsatellite primers for genetic studies. Multiple, independent replications of genotypes and Mendelian checks are both particularly important when using cross-species amplification or when using a low-quality source of DNA.     

Electrophoretic evidence for disomic inheritance and allopolyploid origin of the octoploid Cerastium alpinum (Caryophyllaceae)

The mode of inheritance of six enzyme markers in the octoploid alpine plant Cerastium alpinum was analyzed. Offspring from crosses between heterozygotes showed fixed heterozygosity at malate dehydrogenase-2, phosphoglucoisomerase-2, triosephosphate isomerase-2, and triosephosphate isomerase-3. Phosphoglucomutase-1 also showed fixed heterozygosity except in offspring from one cross. Fixed heterozygosity in five enzyme systems suggests that C. alpinum has originated through at least some allopolyploidization. Offspring from plants heterozygous for two alleles at the menadione reductase-1 (Mr-1) locus did not deviate significantly from a 1:2:1 ratio. The large proportion of homozygotes suggests disomic inheritance because any kind of polysomic inheritance would result in a substantially increased proportion of heterozygotes relative to disomic inheritance. Assuming a diploid model for Mr-1, this locus was used to analyze the population genetic structure within C. alpinum populations. Inbreeding was found in many alpine populations. This may help explain the large genetic distances found among alpine populations in a previous study. The analysis is only based on one segregating locus, and the results should therefore be treated with caution. However, by establishing the mode of inheritance through crosses, we have been able to use a codominant marker in population genetic analysis of an octoploid plant.     

Genetic analysis of the duration of the vegetative period in cotton Gossypium hirsutum L. with background of various nitrogen level in soil

Using Hayman's model of genetic analysis of the F1 hybrids from crosses between early- and late-ripening forms of cotton Gossypium hirsutum L., we examined inheritance of the duration of vegetative period at various contents of nitrogen in soil. Two variants of hybrid plants were studied. With the natural content of soil nitrogen, incomplete directionally dominance of earliness over late ripening with prevalence of additive gene effect of nonallelic interactions was observed. The genetic formulas of this trait proved to change with varying nitrogen nutrition.     

spagedi: a versatile computer program to analyse spatial genetic structure at the individual or population levels

spag e d i version 1.0 is a software primarily designed to characterize the spatial genetic structure of mapped individuals or populations using genotype data of codominant markers. It computes various statistics describing genetic relatedness or differentiation between individuals or populations by pairwise comparisons and tests their significance by appropriate numerical resampling. spag e d i is useful for: (i) detecting isolation by distance within or among populations and estimating gene dispersal parameters; (ii) assessing genetic relatedness between individuals and its actual variance, a parameter of interest for marker based inferences of quantitative inheritance; (iii) assessing genetic differentiation among populations, including the case of haploids or autopolyploids.     

The genetics of breast cancer, population and familial research and segregation analysis

The data on clinico-genealogy studies of 1046 probands with breast cancer and their relatives are presented. The nature of inheritance corresponded to the Mendelian model. As to other families, there is no strong evidence for the monogene model both with complete and incomplete penetrance of mutant homo- and heterozygotes. Penetrance of homozygotes was 7.9-30.5%, this being 2.0-7.3% for heterozygotes. The conclusion is drawn that it is necessary to consider the regularities of inheritance of breast cancer in the light of the multifactorial model.     

Genetic Analysis of the Duration of Vegetative Period in Cotton Gossypium hirsutumL. on Soil with Different Nitrogen Content

Using Hayman's model of genetic analysis of the F₁ hybrids from crosses between early- and late-ripening forms of cotton Gossypium hirsutum L., we examined inheritance of the duration of vegetative period at various contents of nitrogen in soil. Two variants of hybrid plants were studied. With the natural content of soil nitrogen, incomplete directionally dominance of earliness over late ripening with prevalence of additive gene effect of nonallelic interactions was observed. The genetic formulas of this trait proved to change with varying nitrogen nutrition.     

Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans

Differences in the composition of the gut microbial community have been associated with diseases such as obesity, Crohn''s disease, ulcerative colitis and colorectal cancer (CRC). We used 454 titanium pyrosequencing of the V1–V2 region of the 16S rRNA gene to characterize adherent bacterial communities in mucosal biopsy samples from 33 subjects with adenomas and 38 subjects without adenomas (controls). Biopsy samples from subjects with adenomas had greater numbers of bacteria from 87 taxa than controls; only 5 taxa were more abundant in control samples. The magnitude of the differences in the distal gut microbiota between patients with adenomas and controls was more pronounced than that of any other clinical parameters including obesity, diet or family history of CRC. This suggests that sequence analysis of the microbiota could be used to identify patients at risk for developing adenomas.     

Clinico-genetical analysis of colonic cancer. I. Occurrence, frequency in families and segregation analysis

The data on clinico-genealogic studies of colon cancer are presented. 694 families were examined with 432 probands having rectal and 262 colonic carcinoma among them. Clear family accumulation of colon cancer (2.4 +/- 0.35%) as well as other malignant tumors (6.8 +/- 0.6%) (p less than 0.01) was shown among the relatives of the first degree of relation. The values of segregation rates obtained for clinical forms of colon cancer were lower than theoretically expected for simple monogenic types of inheritance. The analysis of incomplete penetration of genotypes showed that, though formally the inheritance of colon cancer and its clinico-anatomical forms may be described by quasi-dominant types of inheritance, the penetration values are very low: from 4.3 to 13.3% for homozygotes and from 2.1 to 6.6% for heterozygotes. It shows that the supposition about the monogenic types of the colon cancer inheritance is doubtful and suggests that the colon cancer is to be regarded on the basis of the multifactorial model.     

Clinico-genetical studies of colonic cancer. II. Genetic analysis of predisposition to colonic cancer

The structure of subjection to different clinical forms of colon cancer and to the morbidity as a whole approximates better the quasi-continued phenotypical model within which the contribution of genetic factors reaches 68-84%, that of incidental medium factors being 16-32%. Genetic study of heterogeneity of colon cancer clinical forms revealed that their pathogenetic community was quite high. However, the origin of colon cancer depends strongly on genetic factors (83.7 +/- 7.3%), in comparison with rectal cancer (67.9 +/- 7.1%). The analysis of colon cancer interrelation with other malignant neoplasms (including specific ones for women--breast and uterus cancer) revealed that the development of another malignant neoplasms was the result of the influence of partially common genes (20-50%) which predetermined the development of colon cancer and other malignant neoplasms. According to the data obtained in this study, the tables of repeated risk have been worked out which may be used for medico-genetic consultation.     

Characterization of two possible forms of type IV collagen from human kidney cortex

Type IV collagen was isolated from human kidney cortex according to the purification of mouse kidney type IV collagen (MKIVC) with minor modifications as described previously [Oikawa, T., et al. (1986) Chem. Pharm. Bull. 34, 789-797]. Chromatography of human kidney type IV collagen (HKIVC) on a column of DEAE-cellulose resulted in its separation into two fractions, i.e., one (HKIVC-1) passed through and the other (HKIVC-2) adsorbed to the column, similar to MKIVC. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Bio-Gel A-5m chromatography revealed that both HKIVC-1 and -2 differed from each other in the ratios of major and minor components. Amino acid analyses also demonstrated that there was a significant difference in the contents of several amino acid residues between both type IV collagens and their 80-kDa components, one of the major ones. These results indicate the possibility that there exist two forms of type IV collagen in human kidney.     

Congenital muscular dystrophies: new aspects of an expanding group of disorders

The congenital muscular dystrophies comprise a genetically and clinically heterogeneous group of disorders characterized by early onset of progressive muscle weakness and often involvement of other organ systems such as the brain and eyes. During the last decade, significant progress has been made to further characterize various forms of congenital muscular dystrophies based on their specific genetic and clinical appearance. This review represents an overview of the recent accomplishments as they relate to clinical, diagnostic, pathogenetic and therapeutic aspects of congenital muscular dystrophies.     

Collapsing SNP genotypes in case-control genome-wide association studies increases the type I error rate and power

Genome-wide association studies are now widely used tools to identify genes and/or regions which may contribute to the development of various diseases. With case-control data a 2x3 contingency table can be constructed for each SNP to perform genotype-based tests of association. An increasingly common technique to increase the power to detect an association is to collapse each 2x3 table into a table assuming either a dominant or recessive mode of inheritance (2x2 table). We consider three different methods of determining which genetic model to choose and show that each of these methods of collapsing genotypes increases the type I error rate (i.e., the rate of false positives). However, one of these methods does lead to an increase in power compared with the usual genotype- and allele-based tests for most genetic models.     

Genetic relationships and reproductive-isolation mechanisms among the Fejervarya limnocharis complex from Indonesia (Java) and other Asian countries

In order to elucidate the genetic relationships and reproductive-isolation mechanisms among the Fejervarya limnocharis complex from Indonesia and other Asian countries, allozyme analyses and crossing experiments were carried out using 208 individuals from 21 localities in eight Asian countries. The allozyme analyses revealed that 17 enzymes examined were controlled by genes at 27 loci, and that 7.9 phenotypes were produced by 5.2 alleles on average. The two species recognized in F. limnocharis sensu lato from Southeast Asia (i.e., F. limnocharis sensu stricto and F. iskandari) were found to occur sympatrically at three localities (Bogor, Cianjur and Malingping), all on Java, Indonesia. Fejervaya iskandari was dominant at each of these localities and showed substantial geographic genetic variation. Laboratory-produced hybrids between F. limnocharis and F. iskandari from Java became underdeveloped and died at the tadpole stage, suggesting that these species are completely isolated by hybrid inviability. Hybrids between topotypic F. limnocharis and the Malaysian and Japanese conspecific populations developed normally to metamorphosis. Likewise, hybrids between topotypic F. iskandari and the Thailand and Bangladesh conspecific populations also showed normal viability throughout larval development. The present allozyme analyses and crossing experiments strongly suggested the presence of two distinct forms, the large type and the small type, in the F. limnocharis complex from Asia, and further subdivision of the large type into the F. limnocharis assemblage and the F. iskandari assemblage. The small type was found in samples from India, Thailand, Bangladesh and Sri Lanka, and included at least three different species. The sample from Pilok, Thailand, was considered to represent an undescribed species.