The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: II. Radiation-Induced Genomic Instability and Bystander Effects In Vivo, Clastogenic Factors and Transgenerational Effects

The use of genome wide single nucleotide polymorphism (SNP) arrays for high resolution molecular cytogenetic analysis using a combination of quantitative and genotype analysis is well established. This study demonstrates that by Mendelian analysis of the SNP genotypes of the parents and a sibling or other appropriate family member to establish phase, it is possible to identify informative loci for each of the four parental haplotypes across each chromosome and map the inheritance of these haplotypes and the position of any crossovers in the proband. The resulting 'karyomap', unlike a karyotype, identifies the parental and grandparental origin of each chromosome and chromosome segment and is unique for every individual being defined by the independent segregation of parental chromosomes and the pattern of non-recombinant and recombinant chromosomes. Karyomapping, therefore, enables both genome wide linkage based analysis of inheritance and detection of chromosome imbalance where either both haplotypes from one parent are present (trisomy) or neither are present (monosomy/deletion). The study also demonstrates that karyomapping is possible at the single cell level following whole genome amplification and, without any prior patient or disease specific test development, provides a universal linkage based methodology for preimplantation genetic diagnosis readily available worldwide.

https://jmg.bmj.com/content/jmedgenet/early/2010/08/30/jmg.2009.069971.full.pdf?jmg_2009_069971v2=&legid=jmedgenet%3Bjmg.2009.069971v2

Karyomapping: a universal method for genome wide analysis of genetic disease based on mapping crossovers between parental haplotypes

background: Chromosomal mosaicism, the presence of two or more distinct cell lines, is prevalent throughout human pre- and post- implantation development and can lead to genetic abnormalities, miscarriages, stillbirths or live births. Due to the prevalence and signifi- cance of mosaicism in the human species, it is important to understand the origins, mechanisms and incidence of mosaicism throughout development. methods: Literature searches were conducted utilizing Pubmed, with emphasis on human pre- and post-implantation mosaicism. results: Mosaicism persists in two separate forms: general and confined. General mosaicism is routine during human embryonic growth as detected by preimplantation genetic screening at either the cleavage or blastocyst stage, leading to mosaicism within both the placenta and fetus proper. Confined mosaicism has been reported in the brain, gonads and placenta, amongst other places. Mosaicism is derived from a variety of

The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans

Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understanding of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of ionising radiation. Other outstanding questions include links between the different non-targeted responses and the variations in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose radiation health effects.

/pdf/non-targeted-effects-of-ionising-radiation-implications-for-4ur0sb5yw9.pdf

Non-targeted effects of ionising radiation—Implications for low dose risk

Purpose of review
The relationship between increasing maternal age and trisomy has been recognized for over 50 years and is one of the most important etiological factors associated with any human genetic disorder. Specifically, the risk of trisomy in a clinically recognized pregnancy rises from about 2–3% for women in their twenties to an astounding 30% or more for women in their forties. Thus, as women approach the end of their child-bearing years, errors of chromosome segregation represent the most important impediment to a successful pregnancy.

/pdf/maternal-age-and-chromosomally-abnormal-pregnancies-what-we-1ong01n0yc.pdf

Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew

The population around the Semipalatinsk nuclear test site in Kazakhstan provides an unparalleled opportunity for the analysis of the genetic risk of ionizing radiation to humans. The Semipalatinsk nuclear test site has been the site for 470 nuclear tests performed by the Soviet Union during the

https://science.sciencemag.org/content/sci/295/5557/1037.full.pdf

Nuclear Weapons Tests and Human Germline Mutation Rate

Down syndrome, characterized by an extra chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 most often originates from the mother, the incidence increases with maternal age, there may be aberrant maternal chromosome 21 recombination and there is a higher recurrence in young women. In spite of intensive efforts to understand the underlying reason(s) for these characteristics, the origin still remains unknown. We hypothesize that maternal trisomy 21 ovarian mosaicism might provide the major causative factor. We used fluorescence in situ hybridization (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in ovarian cells from eight female foetuses at gestational age 14–22 weeks. All eight phenotypically normal female foetuses were found to be mosaics, containing ovarian cells with an extra chromosome 21. Trisomy 21 occurred with about the same frequency in cells that had entered meiosis as in pre-meiotic and ovarian mesenchymal stroma cells. We suggest that most normal female foetuses are trisomy 21 ovarian mosaics and the maternal age effect is caused by differential selection of these cells during foetal and postnatal development until ovulation. The exceptional occurrence of high-grade ovarian mosaicism may explain why some women have a child with Down syndrome already at young age as well as the associated increased incidence at subsequent conceptions. We also propose that our findings may explain the aberrant maternal recombination patterns previously found by family linkage analysis.

/pdf/on-the-origin-of-trisomy-21-down-syndrome-2s495sfqgs.pdf

On the origin of trisomy 21 Down syndrome

Salomaa, S., Lindholm, C., Tankimanova, M. K., Mamyrbaeva, Z. Z., Koivistoinen, A., Hulten, M., Mustonen, R., Dubrova, Y. E. and Bersimbaev, R. I. Stable Chromosome Aberrations in the Lymphocytes of a Population Living in the Vicinity of the Semipalatinsk Nuclear Test Site. Radiat. Res. 158, 591–596 (2002). Translocation analysis using FISH (fluorescence in situ hybridization) chromosome painting was performed to evaluate the magnitude of exposure to ionizing radiation among the human population living close to the Semipalatinsk nuclear test site in Kazakhstan. We studied two generations of people living in villages that were in the path of the radioactive cloud from the first Soviet surface nuclear test performed in August 1949 and from later tests. The older generation (P0) lived in the area at the time of testing, and the younger generation (F1) was exposed to smaller doses from the residual fallout and later tests. In both P0 and F1 generations, similar translocation frequencies were observed...

Stable Chromosome Aberrations in the Lymphocytes of a Population Living in the Vicinity of the Semipalatinsk Nuclear Test Site

During the period between 1949 and 1989 nuclear weapons testing carried out at the Semipalatinsk Nuclear Test Site (STS) in Kazakhstan resulted in local fallout affecting the residents living in the vicinity of the STS. The STS has been the site for more than 450 nuclear tests and more than 1,5 million people were repeatedly exposed to ionizing radiation. In order to gain information on the magnitude of radiation exposure and genetic risk caused by protracted exposure to ionising radiation, a cohort of people exposed to the nuclear test fallout was studied. The villages included in the study are situated along the trail from the first Soviet surface nuclear test in August 1949 and another three surface explosions, which together contributed up to 85% of the collective effective dose to population. Members of 40 three-generation families, comprising 361 individuals, were selected according to preset criteria, interviewed and sampled. A matched control group of 250 persons from a noncontaminated district in South Kazakhstan was also studied. Here we describe the collection of the samples for a bio-sample database with an accompanying registry of background information on the study subjects and present the comparison of demographic data for the exposed and control population.

/pdf/three-generation-study-of-population-living-in-the-vicinity-n1v08kz052.pdf

Three-generation study of population living in the vicinity of the semipalatinsk nuclear test-site - biosample database and population characteristics

Derived from the Greek word for diminution, meiosis means “to halve”. The basic purpose of meiosis is straightforward: to reduce by half the chromosome complement of a diploid cell during gametogenesis (from 46 to 23 in humans) to give rise to haploid gametes. Subsequent fusion of a haploid spermatozoan and a haploid oocyte at fertilization restores the somatic diploid chromosome number in the resulting offspring.



The process of meiosis is conserved through evolution although with marked differences between species and also between sexes. Unlike in mitosis (the division of somatic cells), where daughter cells should have the same genetic component as the parent cell from which they were derived, meiosis serves to effectively “shuffle” the genetic material in two ways, in order to generate an almost infinite genetic variety from the starting chromosomes.



The first of the mechanisms giving rise to variation in alleles is by the independent segregation of the chromosome pairs to the resulting cells; in humans this mechanism alone would give rise to 529 different genetic cell types, and is termed “random assortment”. Perhaps surprisingly, meiotic segregation errors are common in human female meiosis with a large proportion of oocytes having abnormal chromosome numbers (aneuploidy). This does not necessarily impair their fertilization capability, but results in chromosomally unbalanced embryos, which either fail to implant, abort spontaneously, cause intrauterine/perinatal death, or cause the development of liveborn children with chromosome disorders, such as Trisomy 21 Down syndrome.



The second mechanism occurs when chromosome arms exchange homologous regions of DNA through crossing-over, the formation of chiasmata, leading to the recombination of parental alleles. Each individual chromosome pair during meiosis can (and usually does) undergo several different recombination events at any point along their length, and the many different ways in which these can then be resolved into the resulting cells create an “endless” level of variety, such that no two oocytes or sperm from one individual are genetically identical. Chiasmata also serve a most important purpose during meiosis; that of holding homologous chromosomes together until anaphase I.



In this article, we will describe cytogenetic aspects of the process of meiosis, with special reference to the situation in human males and females. Thus, we will summarize achievements in obtaining information on meiosis by microscopic analysis of human germ cells.


Keywords:

meiosis;
gametogenesis;
synaptonemal complex;
chiasma;
crossing-over;
recombination;
aneuploidy

Maira K. Tankimanova

Papers

Nuclear Weapons Tests and Human Germline Mutation Rate

On the origin of trisomy 21 Down syndrome

Stable Chromosome Aberrations in the Lymphocytes of a Population Living in the Vicinity of the Semipalatinsk Nuclear Test Site

Three-generation study of population living in the vicinity of the semipalatinsk nuclear test-site - biosample database and population characteristics

Meiosis and meiotic errors