Beyond nature / nurture: Epigenetics and the legacy of

environment

Michael Arribas-Ayllon

Philosophy Café, Cardiff, 15th February 2010

Part 1Överkalix

The Överkalix Study (2001)• Randomly selected 99 children born in 1905• Their parents and grandparents traced back to birth• Birth dates correlated with regional harvest statistics

– classified periods of ‘poor’, ‘moderate’ and ‘good’ availability to food

• Calculated the availability of food during the child’s ‘Slow Growth Period’ (SGP)– 8-10 years for girls– 9-12 years for boys

• Proband’s age of death used as a variable in a statistical model• Causes of death recorded

Availability of foodCrop failure– 1800– 1809– 1812– 1829– 1821– 1831-6– 1851– 1856– 1867– 1877– 1881– 1888– 1889

Crop abundance– 1799– 1801– 1813-15– 1825-6– 1828– 1841– 1844– 1846– 1853– 1860-1– 1863– 1870– 1876– 1879-80

Findings• There was a deleterious effect on the survival of the proband

if the paternal grandfather was ‘overfed’ at least once during a ‘good’ harvest when he was 9-10 years old

• Probands benefited from the paternal grandfather experiencing at least one ‘poor’ harvest during the SGP when they were 9-12 years old

• Difference in survival between grandchildren, whose paternal grandfather experienced these two extremes, was 32 years

• Moderate availability of food produced no effect

Author’s claims

• ‘Over nutrition’ seems to have altered the DNA when the paternal grandfather and perhaps the paternal grandmother are affected only, but not the maternal ancestor

• The impact ‘skipped’ a generation which could be consistent with genomic imprinting

• Supports the possibility of an intergenerational ‘feedforward loop’

Second study - causes of death

• Cardiovascular disease (n=123)– incidence was lower when PGF exposed to poor

harvest– incidence was higher when PGF exposed to good

harvest

• Diabetes (n=19)– Incidence increased when PGF exposed to poor

harvest– Incidence higher when PGF exposed to good harvest

Author’s claims

• Nutrition-related circumstances has a transgenerational association on cardiovascular and diabetes-related deaths

• Transmission follows the paternal line• No evidence for a specific mechanism

ALSPAC study (2006)

1. Survey of 14,024 pregnancies– fathers who reported smoking (n=9886)– age of exposure to smoking (SGP)– offspring measured for BMI at 7 and 9 years

2. Reanalysed Överkalix data for sex-specific effects– re-examined data pertaining to paternal grandmother

Findings

ALSPAC• Found strong association between age of paternal father

smoking (onset) and the BMI of boys at 9 years

Överkalix• The effect of food supply on the paternal grandmother

during SGP (0-3 years) showed the largest transgenerational response:– two-fold higher mortality rate when paternal grandmother

experienced food abundance

Author’s claims• Found a clear sex specific, male-line transgenerational effect across

both data sets• Little known about the specific mechanism responsible for effect• They hypothesise that sex chromosome (X and Y) may play a role:

– father to son and paternal grandfather to grandson (Y chromosome)– grandmother to granddaughter (X chromosome)

• SGP is a critical period of development• So a one-off environmental event affecting prepubescent boys can

alter the phenotype of their sons and grandson– supported by animal studies

Do genes have memory?

• In the past low birth weight and morbidity has been linked to maternal undernutrition

• The molecular mechanism is not know but an increasingly popular hypothesis is ‘epigenetics’

• Genomic imprinting– ‘switching’ genes on or off

Part 2Nature / Nurture

N / N debate is a tedious ritual of discussion

• Unreasonably persistent dichotomy• Two common claims:

– N / N = universal– not N or N, but both

• Product of 19th c.• Language of genetics

A ‘convenient jingle’“The phrase ‘nature and nurture’ is a convenient jingle of words, for it separates under two distinct heads the innumerable elements of which personality is composed. Nature is all that a man brings with himself into the world; nurture is every influence from without that affects him after his birth ... When nature and nurture compete for supremacy on equal terms ... the former proves to be the stronger ... [although] neither is self-sufficient” (Galton, 1874: 12).

Francis Galton

Classical genetics

• Particulate theory of inheritance• Powerful model capable of explaining:

– transmission of hereditary characteristics– biodiversity over time– dominant and recessive inheritance

• Also amenable to:– relatively simple universal laws– reductionist explanations of inheritance

Gregor Mendel

Lamarckism

• Soft inheritance• Folk wisdom• Partly accommodated by Darwin (pangenesis)• Galton sought to disprove Darwin’s theory• Eventually ruled out by Mendelian genetics• Germ plasm theory (1892)• Weismann’s barrier

Jean-Baptiste Lamarck

Grammar of Science

If the views of Weismann be correct—if the bad man can by the influence of education and surroundings be made good, but the bad stock can never be converted into good stock—then we see how grave a responsibility is cast at the present day upon every citizen, who directly or indirectly has to consider problems relating to the state endowment of education, the revision and administration of the Poor Law, and, above all, the conduct of public and private charities (Pearson, 1892: 26-7).

Karl Pearson

The return of epigenetics

• Epigenome introduces another level of complexity

• ‘Sits on top’ of the genome

• Challenges natural selection as the only mechanism of heredity

• Specific environmental exposures (drugs, alcohol, psychosocial stress, etc) or disease states (depression, etc) may be correlated with specific epigenomic changes

Ethics of epigeneticsEpigenetics may lead to unique ethical challenges:– intensify obligations concerning lifestyle

decisions– increase blame arising from choice– liability for future illness in offspring– multigenerational liability for mortgages,

employment or insurance– increase discrimination?– privacy of information regarding

epigenetic influences– compensation for exposure to

environmental risks– highlight social inequalities