HERITABLE EFFECTS OF RADIATION

Sneha George

BASICS OF GENETICS

• CHROMOSOME

- Contains long threadlike structures called DNA- Carries all the information that specifies a

particular human with his/her individual characteristics

- 22 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 gene

• Human 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.

MUTATION

• Any 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 Radiation

• Adverse 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 Chromosomal Multifactorial

Mendelian Inheritance

• Autosomal dominant

• Autosomal recessive

• X-linked

Autosomal dominant

• Expressed in the first generation after its occurrence.

• Eg’s - Polydactyly, achondroplasia, Marfan’s syndrome and Huntington's chorea.

Autosomal recessive

• Require that the gene be present in duplicate to produce the trait

• Mutant gene must be inherited from each parent

• Eg’s - Sickle-cell anemia, cystic fibrosis, and Tay-Sachs disease.

X-linked

• Mutations in genes located on the X-chromosome.

• Eg’s - 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 Changes

• Abnormalities either in the structure of the chromosomes or in the number of chromosomes

• Down's syndrome• 40% of the spontaneous abortions• 6% of stillbirths• Radiation is much more effective at breaking

chromosomes than in causing errors in chromosome distribution.

Multifactorial

• Known to have a genetic component• Transmission pattern not simple Mendelian• Congenital abnormalities: cleft lip with or

without cleft palate; neural tube defects• Adult onset: diabetes, essential hypertension,

coronary heart disease• Interaction with environmental factors

RADIATION-INDUCED HEREDITARY EFFECTS IN FRUIT FLIES

• 1927 – Müller - 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 because

– A low doubling dose (5-150 R) for mutations

– Hereditary effects were cumulative

– Little 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 MICE

• Russell and Russell - Oak Ridge National Laboratory

• To determine specific locus mutation rates in the mouse

• Megamouse project - 7 million mice• An inbred mouse strain was chosen in which

seven specific mutations occur, 6 involving change of coat color & 1 as stunted ear.

• Five major conclusions1. The radiosensitivity of different mutations varies

by a significant factor of about 352. Dose rate effect was evident.– Chronic dose exposure induces fewer mutations– Acute dose exposure induces more mutation– This is in contrast with Drosophila

3. The oocytes are exquisitely radiosensitive.4. The genetic effects of a given radiation dose can

be reduced greatly if a time interval is allowed between exposure and conception.

5. The estimate of the doubling dose adopted by BEIR V and UNSCEAR 88 is 1 Gy.

RADIATION-INDUCED HEREDITARY EFFECTS IN HUMANS

• Two 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 Cells

• Resistant– Post-spermatogonial cells

• Sensitive– Stem cells

• Temporary sterility– 15 rad (0.15 Gy)– 40 rad/year (0.4 Gy/yr)

• Permanent sterility– 350-600 rad (3.5 to 6 Gy)– 200 rad/yr (2 Gy/yr)– No significant hormonal

imbalance

• Resistant– Post-oogonial cells

• Sensitive– follicles

• Permanent sterility– 250-600 rad (2.5 to 6 Gy)– 20 rad/yr (0.2 Gy/yr)– Pronounced hormonal

imbalance

Males Females

Two Correction Factors

• Not 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 - Human

• Children 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 RISKS• Dose 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 2007

• The level of concern involving radiation carcinogenesis has increased as more and more solid tumours have appeared in the Japanese A-bomb survivors

EPIGENETICS• Changes in gene expression that takes place

without a change in the DNA sequence• The 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 modification

• Expression of an imprinted gene in the present generation depends on the environment that it experienced in the previous generation

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