Evidence for an elevated frequency of in vivo somatic cell mutations in ataxia telangiectasia.

Somatic cell mutation frequency in vivo was measured in individuals with high cancer risk who were from ataxia telangiectasia (A-T) families. The assay for somatic mutation measures the frequency of variant erythrocytes which are progeny of erythroid precursor cells with mutations that result in a loss of gene expression at the polymorphic glycophorin A (GPA) locus. Samples from 14 of 15 A-T homozygotes showed high frequencies of GPA gene expression-loss variant cells with normal expression of only one of the two alleles at the GPA locus (i.e., GPA hemizygous variant cells). The mean elevation of the frequency of hemizygous variant cells over those in normal controls and unaffected family members was 7-14-fold. A-T homozygotes also showed an increase in the frequency of cells in which one allele at the GPA locus had lost expression and in which the remaining allele was expressed at a homozygous level (i.e., GPA homozygous variant cells). Family members who are obligate A-T heterozygotes did not appear to have a significantly elevated frequency of GPA hemizygous or homozygous variant cells. These indications of elevated in vivo frequencies of variant erythrocytes in A-T homozygotes support a causal link between susceptibility to somatic mutation and susceptibility to cancer.     

Haldane's rule and somatic mutations]

Haldane's rule stating that viability and fertility in the heterogametic sex of hybrids are lower than in the homogametic sex is explained on the basis of the assumption that diploidy is aimed at protecting individuals having large body size and large genomes from somatic mutations. The presence of hemizygous sex chromosomes, which are effectively haploid in the heterogametic sex, results in the phenotypic expression of all deleterious somatic mutations arising in them. In the homogametic sex, somatic mutations that affect one out of two identical sex chromosomes are not expressed because the unaffected chromosome functions normally. Thus, the heterogametic sex is more sensitive to the harmful effect of somatic mutations. In hybrids, this difference may be critical. Consequently, when genetic distance between hybridizing species increases, the heterogametic sex of hybrids loses viability and fertility earlier than the homogametic sex, which agrees with Haldane's rule. On the basis of Haldane's rule and data on the small size of natural hybrid zones, restrictions on maximum heterozygosity compatible with viability were established.     

Estimating cell depth from somatic mutations

The depth of a cell of a multicellular organism is the number of cell divisions it underwent since the zygote, and knowing this basic cell property would help address fundamental problems in several areas of biology. At present, the depths of the vast majority of human and mouse cell types are unknown. Here, we show a method for estimating the depth of a cell by analyzing somatic mutations in its microsatellites, and provide to our knowledge for the first time reliable depth estimates for several cells types in mice. According to our estimates, the average depth of oocytes is 29, consistent with previous estimates. The average depth of B cells ranges from 34 to 79, linearly related to the mouse age, suggesting a rate of one cell division per day. In contrast, various types of adult stem cells underwent on average fewer cell divisions, supporting the notion that adult stem cells are relatively quiescent. Our method for depth estimation opens a window for revealing tissue turnover rates in animals, including humans, which has important implications for our knowledge of the body under physiological and pathological conditions.     

Statistical analysis of pathogenicity of somatic mutations in cancer

Recent large-scale sequencing studies have revealed that cancer genomes contain variable numbers of somatic point mutations distributed across many genes. These somatic mutations most likely include passenger mutations that are not cancer causing and pathogenic driver mutations in cancer genes. Establishing a significant presence of driver mutations in such data sets is of biological interest. Whereas current techniques from phylogeny are applicable to large data sets composed of singly mutated samples, recently exemplified with a p53 mutation database, methods for smaller data sets containing individual samples with multiple mutations need to be developed. By constructing distinct models of both the mutation process and selection pressure upon the cancer samples, exact statistical tests to examine this problem are devised. Tests to examine the significance of selection toward missense, nonsense, and splice site mutations are derived, along with tests assessing variation in selection between functional domains. Maximum-likelihood methods facilitate parameter estimation, including levels of selection pressure and minimum numbers of pathogenic mutations. These methods are illustrated with 25 breast cancers screened across the coding sequences of 518 kinase genes, revealing 90 base substitutions in 71 genes. Significant selection pressure upon truncating mutations was established. Furthermore, an estimated minimum of 29.8 mutations were pathogenic.     

Evidence for the presence of somatic mitochondrial DNA mutations in right atrial appendage tissues of coronary artery disease patients

Coronary artery disease (CAD) is a multifactorial disease with the underlying involvement of environment, life style and nuclear genetics. However, the role of extranuclear genetic material in terms of somatically acquired mutations in mitochondrial tRNA and protein coding genes in the initiation or progression of CAD is not well defined. Hence, in the present study, right atrial appendage tissues and matched blood samples of 150 CAD patients were screened for mutations in nucleotide regions encompassing the Cytochrome c oxidase subunit II (MT-CO2), tRNA lysine (MT-TK), ATP synthase F0 subunit 8 (MT-ATP8) and Cytochrome b (MT-CYB) genes of mitochondrial DNA. We have found 9 different somatic mutations in 6 % of the CAD patients. Out of these mutations, 4 each were localized in MT-TK gene (T8324A, A8326G, A8331G and A8344G) and MT-CYB genes (T15062C, C15238A, T15378G and C15491G) in addition to one mutation in non-coding region 7 (A8270T) of mitochondrial genome. In addition, we noticed that majority (85.3 %) of CAD patients showed double repeats of germ-line “CCCCCTCTA” intergenic sequence between MT-CO2 and MT-TK genes. Our in-silico investigations of missense mutations revealed that they may alter the free energy and stability of polypeptide chains of MT-CYB protein of complex III of mitochondrial respiratory chain. Based on our study findings, we hypothesize that the somatically acquired variations in MT-TK and MT-CYB genes may negatively impact the energy metabolism of cardiomyocytes in right atrial appendage tissues and contribute in the cardiac dysfunction among CAD patients. In conclusion, our findings may be likely to have potential implications in understanding the disease pathophysiology, diagnosis as well as for the better therapeutic management of CAD patients.     

A comprehensive catalogue of somatic mutations in cancer genomes

This Hot Topics contribution considers two recently published papers that demonstrate the utility of advanced DNA sequencing technologies for identifying classes of mutations other than base substitutions. Data are presented from genome analyses of immortalized cell lines derived from a malignant melanoma and a small cell carcinoma of the lung. Among other observations the studies suggest the operation of novel DNA repair mechanisms or modes.     

Evidence against somatic association in hexaploid wheat

In mitotic interphase nuclei, nucleolus-organizing regions of homologous chromosomes lay no closer to each other than nucleolus-organizing regions of non-homologous chromosomes. — Mitotic metaphase studies of distances between satellites and also between telocentrics showed no greater nearness of homologues than of non-homologues. — These studies fail to support the concept of somatic association in hexaploid wheat.     

Interphase cytogenetics in estimation of genomic mutations in somatic cells

The review considers the current state, possibilities, and perspectives of using interphase cytogenetics in the estimation of genomic mutations in human and animal somatic cells for aims of genetic toxicology and genetic instability analysis. Possible mechanisms underlying action of mutagens causing numeric chromosome aberrations are discussed.Translated from Genetika, Vol. 41, No. 1, 2005, pp. 5–16.Original Russian Text Copyright © 2005 by Timoshevsky, Nazarenko.     

Interphase cytogenetics in estimation of genomic mutations in somatic cells

The review considers the current state, possibilities, and perspectives of using interphase cytogenetics in the estimation of genomic mutations in human and animal somatic cells for aims of genetic toxicology and genetic instability analysis. Possible mechanisms underlying action of mutagens causing numeric chromosome aberrations are discussed.     

Interactions between somatic mutations and plant development

It is hypothesised that somatic mutations are an important source of genetic variance within long-lived plant individuals, and that shoot ontogeny and sexual reproduction are two processes that decrease the mutation load of the shoot population and the offspring. This paper focuses on the way in which sympodial and monopodial shoot branching may influence intra-plant genetic variation and on the role of physiological integration between plant modules for the phenotypic expression of this variation. I also discuss some possible consequences of the interaction of somatic mutations and shoot ontogeny for the study of seedling recruitment and phenotypic plasticity in plant populations.     

In vivo somatic mutations in Werner’s syndrome

The frequencies of mutant erythrocytes with loss of heterozygosity at the glycophorin A (GPA) locus and mutant CD4⁺ T cells lacking surface expression of the T-cell receptor αβ (TCR)/CD3 complex were measured by flow cytometry for Japanese Werner’s syndrome (WRN) patients. The hemizygous and homozygous GPA mutant frequencies (GPA Mfs) and the TCR/CD3-defective mutant frequency (TCR Mf) in WRN patients were found to be significantly higher than those in normal controls in the same age range. However, because these Mfs in the patients are only about twice those in controls, it is difficult to conclude that the WRN gene mutations cause instability of somatic genes. This contrasts markedly with Bloom’s syndrome (BLM) patients, whose GPA and TCR Mfs were previously reported to increase about 50- and 15-fold, respectively. The difference in Mfs is one aspect of the large variation in the phenotype observed between WRN and BLM patients, suggesting a different role of the responsible genes, both of which belong to the RecQ DNA helicase gene family, in the control of somatic mutagenesis. Received: 8 June 1998 / Accepted: 21 August 1998     

Evidence from somatic cells for crossing-over in humans

Chromosomal and gene marker studies of somatic cells in a family with multiple chromosome translocations show apparent instability of the translocations in transmission from generation to generation. This instability is attributed to meiotic crossing-over between the involved chromosomes. Technical advances in chromosome analysis combined with human gene map information in the study of this unusual family demonstrate for the first time that crossing-over involves exchange of chromatin between nonsister chromatids of homologous chromosomes.     

Radiation-induced lethal mutations appearing in cells of somatic tissue in Drosophila

Exposure of 3-hour drosophila male embryos to gamma-radiation during the topographic segregation of the germ anlage nuclei caused recessive sex-linked lethals in somatic cells only. The selectivity of the screening was determined by the ratio of mutation frequencies induced in embryos and adult males. Analysis of lethal mutations shows that a minimal rate of the divergence between germinal and somatic patterns of the cell development is observed in the embryogenesis, the 3d instar larva and prepupa, and maximal in the 1st and 2nd larva and pupa.