MEDICAL & ENVIRONMENTAL IMPLICATIONS OFDEVELOPMENTAL GENETICS

c) Phenotypic plasticity: Polyphenism– nutritional,

seasonal, DIET AND DNA METHYLATION,predator induced polyphenism, Environment dependent sexual phenotype, learning - Adaptive nervous system.

UNIT I : DEVELOPMENT AND ENVIRONMENT

NETHRAVATHI RGN113011IV sem, MSc. GENETICS

Development and Environment:

• Everything needed for producing a phenotype is not prepackaged in the fertilized egg.

• Environmental factors, such as diet, temperature, conspecifics, and predators can initiate alternative developmental trajectories in the developing organism, leading to different phenotypes.

• 'Development and environment are two sides of the same coin'

ENVIRONMENTAL

I class II class

Biotic or abiotic sources thatare separate from and independent of the developing organism

symbiotic organisms thatmay or may not be integral to the organism, and which,when present, constitute part of the development signalingapparatus.

ENVIRONMENTAL SIGNAL

FACULTATIVESIGNAL

OBLIGATORY SIGNAL

Environmental agents help determine a particular developmental trajectory out of a suite of possible trajectories made possible by the genome.

The organism has outsourced a critical developmental cue to an environmental agent and cannot develop without thatexternal cue.

Eg: DiapauseEg: Predator present / absent

Genetic sources of variation have been catalogued by ARTHUR 2004.

1. Heterotypy (change in the protein-encoding region of the gene being expressed)

2. Heterochrony (change in the timing of gene expression)

3. Heterotopy (change in the location of gene expression)

4. Heterometry (change in the amount of gene product)

Variation can arise from genetic or environmental sources.

Gilbert and Epel, 2009:

• Epigenetic sources of variation include biotic and abioticfactors in the environment, symbionts, and epialleles.

• The environment can be an important source of selectable variation.

• Here, the environment is acting in both an instructive and a selective manner, informing the production of a phenotype that is then subject to selection.

West-Eberhard, 2003

The genotype can be seen as providing a repertoire of possible phenotypes, and the environment can be said to act differentially and instructively. This is seen in the phenomena of PHENOTYPIC PLASTICITY.

Phenotypic plasticity, often called “DEVELOPMENTAL PLASTICITY” when observed in embryonic and juvenile stages, is the ability of an organism to react to an environmental input with a change in form, state, movement, or rate of activity.

DEVELOPMENTAL PLASTICITY

DEVELOPMENTAL PLASTICITY

REACTION NORM POLYPHENISM

The genome encodes the potential for a continuous rangeof potential phenotypes, and the environment the individual encounters determines the phenotype (usually the most adaptive one).

Discontinuous phenotypes elicited by the environment.

Eg; the length of the male’s horn in some beetle species is determined by the quantity and quality of food the larva gets to eat beforeMetamorphosis.

Eg; sex determination inmany reptiles, where one range of temperatures will induce female development in the embryo, while another set of temperatureselicit male development

DEVELOPMENTAL PLASTICITY

• Developmental plasticity in animals was well known to the experimental embryologists of the late 19th century.

• In 1894 volume, The Biological Problem of Today: Preformation or Epigenesis?, Oskar Hertwig summarized the studies demonstrating that development involved not only the interactions between embryonic cells but also involved important interactions between developing organisms and their environments.

• He cited numerous cases where the phenotype was directed by the environment, e.g.; nutrition-dependent production of workers and queens in ant colonies

DIET• Diet plays critical roles in the development of

numerous organisms.

• Diet is largely responsible for the formation of fertile “queens” in several species of ants, wasps, and bees.

• Here, each larva has the genetic potential to become either a sterile worker or an ovary-bearing queen.

• Only those larvae fed adequately can become queens.

Gluckman and Hanson 2005:

Juvenile diet is to enables the organism to make “predictive adaptive responses” such that its development matches the environmental conditions.

Emlen and Nijhout 1999; Kijimoto et al. 2010:

• In certain species of dung beetles (such as Onthophagus taurus), the amount and quality of food is the major determinant of male horn length.

Diet DNA methylation

• DNA methylation is an enzymatic modification [the addition of a methyl group to cytosines in CpG(cytosine/guanine) pairs] carried out by DNA methyltransferases.

• The added methyl group does not affect the base pairing itself, but the protrusion of methyl groups into the DNA major groove can affect DNA–protein interactions.

DNA methylation ????

History (DNA methylation)

DNA methylation were first discovered in studies during the 1980s

1. Ehrlich and Wang 1981

2. Laird and Jaenisch 1994

3. X-chromosome inactivation by Avner and Heard in 2001

4. Cancer by Feinberg and Tycko in 2004

5. Genomic imprinting by Verona et al. 2006

Alterations in DNA methylation patterns are the best understood epigenetic cause of disease

Robertson 2002

• Methylated CpGs are usually associated with silenced DNA, can block methylation sensitive proteins from binding to the DNA and are subject to high mutation rates.

• DNA methylation patterns are established and maintained by DNMTs, enzymes that are essential for proper gene expression patterns.

Diet and DNA methylation

• Several bioactive food components can modulate DNA methylation

• The carbon metabolism pathway influences the supply of donor methyl groups and consequently the biochemical pathways of methylation processes

• Eg; vitamin B12, vitamin B6, FOLATE, methionine, and choline

THF = tetrahydrofolateDNA METHYALTION PATHWAY

THF = tetrahydrofolate

DHF = dihydrofolateTHF = tetrahydrofolate

• THF = tetrahydrofolate• GHMT = Glycogen Hydroxy Methyl Transferase• a carbon unit from serine or glycine is transferred to tetrahydrofolate to form 5,10-

methylenetetrahydrofolate (Scott and Weir 1998).

THF = tetrahydrofolate5,10-CH2 THF = 5,10-methylene tetrahydrofolate

• Vitamin B6 is a necessary co-factor for glycine hydroxymethyltransferase in thesynthesis of 5,10-methylenetetrahydrofolate (Ross 2003)

5,10-CH2 THF = 5,10-methylene tetrahydrofolateIt can be used for the synthesis of thymidine (Ross 2003)

5,10-CH2 THF = 5,10-methylene tetrahydrofolateIt can be oxidized to formyltetrahydrofolate for the synthesis of purines (Ross 2003)

5,10-CH2 THF = 5,10-methylene tetrahydrofolatemethyl THF = 5 -methyl tetrahydrofolateIt can be reduced to 5-methyltetrahydrofolate (Ross 2003)

methyl THF = 5 methyl tetrahydrofolateIt can be used to methylate homocysteine to form methionine(Ross 2003)

B12 = vitamin B12MS = methionine synthasemethyl THF = 5 methyl tetrahydrofolate

vitamin B12–dependent enzyme methionine synthase (MS) catalyzes the synthesis of methionine from homocysteine (Ross 2003)

SAM = S-Adenosyl MethionineMAT = methionine adenosyltransferase

Methionine is subsequently converted to S-adenosylmethionine (SAM) by an ATP-dependent transfer of adenosine to methionine via methionine adenosyltransferase (Ross 2003)

SAM = S-Adenosyl MethionineMAT = methionine adenosyltransferaseSAM can then donate methyl groups to more than 80 biological methylationreactions,including DNA methylation (Choi & Mason 2001)

EXPERIMENTAL EVIDENCES;

Within the embryo, the diet can alter the DNA methylation pattern of particular genes involved in fat and carbohydrate synthesis.

Experimental evidence : 1

Experimental evidence : 2

Mothers during gestation (Mouse)

low protein diet Normal protein diet

different pattern of liver gene methylation

differences in methylation changed the metabolic profile of the mouse’s liver

Result

Experimental evidence : 3

McGill crew male mice Folate rich diet

Folate poor diet

Assessed the epigenetic changes

offspring with birth defects, including craniofacial and musculoskeletal abnormalities

Genome-wide DNA methylationanalysis

dysregulation of genes involved in development, chronic diseases such as cancer, diabetes, autism, and schizophrenia

4, 300 genes are differentially expressed in offspring placenta

321

4. Animal studies have shown that folate deficiency causes DNA hypomethylation prior to the development of tumors (Jacob et al. 1998).

5. DNA hypomethylation has also been found in the lymphocytes of humans on low dietary folate and can be reversed by folate repletion (Trasler et al. 2003).

6. zinc deficiency (Wallwork and Duerre 1985) and retinoic acid excess (Rowling et al. 2002) has been shown to reduce the use of methyl groups from SAM in rat liver and to result in global DNA hypomethylation.

Experimental evidence….

7. both absences and excesses of dietary arsenic have been shown to cause global hypomethylation in rat liver (Uthus1993)

8. In a rat model of hepatocellular carcinoma, a choline-deficient diet induced hypomethylation of CpG sites in the c-myc gene as well as the overexpression of this gene (Tsujiuchi et al. 1999)

9. vitamin C deficiency has been linked with DNA hypermethylation in lung cancer (Haliwell 2001).

10. The intake of genistein was positively correlated with changes in prostate DNA methylation at the CpG islands of specific mouse genes, as evaluated using mouse differential hybridization arrays (Day et al. 2002).

Experimental evidence….

CONCLUSION

• DNA methylation offers an important window into understanding the role of interactions between the environment and the genome in causing disease, and in modulating these interactions to improve human health

• studies suggest that the effects of diet on DNA methylation are highly complex, appear to depend on cell type, target organ, and stage of transformation and are gene- and site-specific.

• There may be optimum amounts of certain dietary components that enable normal DNA methylation.

References:

• http://cdn.intechopen.com/pdfs-wm/32809.pdf (Ali A. Alshatwi, Effects of Dietary Nutrients on DNA Methylation and Imprinting )

• http://epigenie.com/dna-methylation-and-diet-you-are-also-what-your-father-ate/

• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325941/pdf/pone.0034857.pdf Snell-Rood EC, Moczek AP (2012) Insulin Signaling as a Mechanism Underlying Developmental Plasticity: The Role of FOXO in a Nutritional Polyphenism. PLoS ONE 7(4): e34857. doi:10.1371/journal.pone.0034857

• http://epigenie.com/dna-methylation-and-diet-a-lot-to-chew-on/

• Scott F.Gilbert, Developmental Biology, 10th edition.

THANK YOU