HERITABLE EFFECTS OF RADIATION

HERITABLE EFFECTS OF RADIATION Sneha George

BASICS OF GENETICSCHROMOSOME

Contains long threadlike structures called DNACarries all the information that specifies a particular human with his/her individual characteristics22 pair of autosomes + 1 pair of allosomes

DNA

Double helix

Organic bases

Sugar-phosphate backbone

Gene Finite segment of DNA specified by an exact sequence of bases.Locus Position of a geneHuman genome DNA of chromosomes + DNA of mitochondria.6 billion base pairs of DNA.Total no of protein encoding genes 25,000 to 50000/haploid set of chromosomes.

MUTATIONAny change in chromosomes, their genes, and their DNA.

Include an array of changes in DNA, such as deletion, rearrangement, breakage in the sugar-phosphate backbone, and base alterations.

Heritable Effects of RadiationAdverse health effects in descendants due to mutations induced in germ cells.Radiation does not produce new unique mutations, but increases the incidence of the same mutations that occur spontaneously.Information on the genetic effects of radiation comes almost entirely from animal experiments.

HERITABLE DISEASES

Mendelian Inheritance

Autosomal dominant

Autosomal recessive

X-linked

Autosomal dominantExpressed in the first generation after its occurrence.

Egs - Polydactyly, achondroplasia, Marfans syndrome and Huntington's chorea.

Autosomal recessiveRequire that the gene be present in duplicate to produce the traitMutant gene must be inherited from each parentEgs - Sickle-cell anemia, cystic fibrosis, and Tay-Sachs disease.

X-linkedMutations in genes located on the X-chromosome.

Egs - Hemophilia, color blindness, and a severe form of muscular dystrophy

67% are caused predominantly by point mutations (base-pair changes in the DNA)22% by both point mutations and DNA deletions within genes (i.e., they are intragenic)13% by intragenic deletions and large multilocus deletions.

Chromosomal ChangesAbnormalities either in the structure of the chromosomes or in the number of chromosomesDown's syndrome40% of the spontaneous abortions6% of stillbirthsRadiation is much more effective at breaking chromosomes than in causing errors in chromosome distribution.

MultifactorialKnown to have a genetic componentTransmission pattern not simple MendelianCongenital abnormalities: cleft lip with or without cleft palate; neural tube defectsAdult onset: diabetes, essential hypertension, coronary heart diseaseInteraction with environmental factors

RADIATION-INDUCED HEREDITARY EFFECTS IN FRUIT FLIES1927 Mller - exposure to x-rays could cause readily observable mutations in the fruit fly, Drosophila melanogaster.Included a change of eye color from red to white, the ebony mutant with its jet-black color, the vestigial wing mutant, and the recessive lethal mutation.

Hereditary changes were considered the principal hazard of exposure to ionizing radiation becauseA low doubling dose (5-150 R) for mutationsHereditary effects were cumulativeLittle was known of the carcinogenic potential of low doses of radiation.The doubling dose is the dose required to double the spontaneous mutation rate.

RADIATION-INDUCED HEREDITARY EFFECTS IN MICERussell and Russell - Oak Ridge National LaboratoryTo determine specific locus mutation rates in the mouseMegamouse project - 7 million miceAn inbred mouse strain was chosen in which seven specific mutations occur, 6 involving change of coat color & 1 as stunted ear.

Five major conclusionsThe radiosensitivity of different mutations varies by a significant factor of about 35Dose rate effect was evident.Chronic dose exposure induces fewer mutationsAcute dose exposure induces more mutationThis is in contrast with DrosophilaThe oocytes are exquisitely radiosensitive.The genetic effects of a given radiation dose can be reduced greatly if a time interval is allowed between exposure and conception.The estimate of the doubling dose adopted by BEIR V and UNSCEAR 88 is 1 Gy.

RADIATION-INDUCED HEREDITARY EFFECTS IN HUMANSTwo basic pieces of data are needed:Base-line spontaneous mutation rate in humans 738,000 per million.Doubling Dose (1 Gy, or 100 rad).

Radiation and Sex CellsResistantPost-spermatogonial cellsSensitiveStem cellsTemporary sterility15 rad (0.15 Gy)40 rad/year (0.4 Gy/yr)Permanent sterility350-600 rad (3.5 to 6 Gy)200 rad/yr (2 Gy/yr)No significant hormonal imbalanceResistantPost-oogonial cellsSensitivefolliclesPermanent sterility250-600 rad (2.5 to 6 Gy)20 rad/yr (0.2 Gy/yr)Pronounced hormonal imbalanceMalesFemales

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Two Correction FactorsNot all mutations lead to disease.The mutation component (MC):0.3 for autosomal dominant.0.0 for autosomal recessive.0.01-0.02 for chronic multifactorial.The 7 specific locus mouse mutations are not representative; they are genes not essential for viability. Only a small proportion of human genes, when mutated, would result in live births.

Hereditary Effects of Radiation - HumanChildren of the survivors of Hiroshima and Nagasaki have been studied for untoward pregnancy outcomes, death of live-born children, sex chromosome abnormalities, electrophoretic variants of blood proteins.

Though no genetic indication is statistically significant, the average doubling dose is 156 rem (1.56 Sv).

MUTATIONS IN THE CHILDREN OF THE A-BOMB SURVIVORS

CHANGING CONCERNS FOR RISKSDose limit of radiation workers reduced to 50mSv per year(by ICRP in 1956)The level of concern regarding genetic effects has declined steadily as a consequence the percentage of radiation detriment attributed to the genetic component in view of ICRP has declined from 100% in 1955 to 4% in 2007The level of concern involving radiation carcinogenesis has increased as more and more solid tumours have appeared in the Japanese A-bomb survivors

EPIGENETICSChanges in gene expression that takes place without a change in the DNA sequenceThe changes result from mainly these molecular modifications - DNA methylation which takes place at the carbon 5 position of cytosine in CpG dinucleotides - Changes to chromatin packaging of DNA by post translational histone modifications

Pre natal and early postnatal environmental factors can result in altered epigenetic programming and subsequent changes in the risk of developing disease later in life

Environmental changes studied include nutritional supplements, xenobiotic chemicals and exposure to ionizing radiation

Radiation studies showed that exposure of adult mice led to transgenerational genome instability in the offspring resulting from a significant loss of DNA methylation in somatic tissue.In addition there is some evidence from animal studies that epigenetic alterations may be inherited trans- generationally thereby affecting the health of future generations

IMPRINTED GENES

Expression is from only one parental allele with the other allele silenced this leads to a non mendelian germ line inherited form of gene regulation that involves heritable DNA methylation and histone modificationExpression of an imprinted gene in the present generation depends on the environment that it experienced in the previous generation

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