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Transgenerational Genetic Effects - a Newly Discovered Mode of Inheritance

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The study of epigenetics has undoubtedly emerged as one of the hottest fields of research over the past decade. Interest in epigenetics has arisen as researchers endeavor to reveal the underlying causes of phenotypic variation and common diseases despite technological advances allowing for the characterization of genetic variants and their heritability.

A recent article in Augusts issue of Epigenomics by Joseph Nadeau and colleagues at the Case Western Reserve University (Cleveland, Ohio) has reported that phenotypic variation are in some part attributed to the action of genetic variants in previous generations. This reinforces the general sense that traits and diseases 'run' in families as these transgenerational genetic actions act as another mode of inheritance which in turn contribute to 'missing heritability' and variation.

Familial occurrence remains the single strongest factor to account for variation in disease risk. Genotype-phenotype relationships have been central to many studies of heritable traits. These studies help elucidate that an individual affected with a genetic disease or condition dramatically increases the risk for everyone else in the family. Finding these specific genes proves difficult, hence 'missing heritability'.

This study involving chromosomes substitution strains (CSS) of mice as model organisms tested both the frequency of the affected traits and the strength of their phenotypic effects by observing the genetically inherited phenotypic effects from the father's Y chromosome on female offspring. Because daughters do not inherit their fathers' Y chromosome, any traits that are attributable to the Y must be transgenerational rather than conventional inheritance. The carefully selected chromosome substitution method allowed for the control of potentially confounding genetic, social and environmental factors.

"A CSS is made by substituting a single chromosome from a donor strain on an inbred host strain. The resulting strain is identical to the original inbred host strain except for homozygosity for the substituted chromosome"

Daughters (XX) do not inherit the Y chromosome and therefore should not share the phenotype of CSS fathers. However results from this study found that although daughters were genetically identical to females from the host strain, their phenotype is attributed to this transgenerational genetic effect. In this first test for the generality of heritable epigenetic changes, the authors found that the frequency and strength of phenotypic effects resulting from transgenerational and conventional inheritance were comparable in frequency and strength, suggesting that this unconventional mode of inheritance rivals conventional genetics in its impact on biological variation and disease risk.

‘‘We found striking evidence for frequent and strong phenotypic changes in daughters that are attributable in a transgenerational genetic manner to the parental Y chromosome.’’

In addition to phenotype screening, a carefully designed behavioural test strongly suggested that transgenerational rather than social and environmental factors lead to altered behaviour in the daughters from CSS males.

‘‘These results are especially surprising given the relatively small number of genes on the Y chromosome’’ Nadeau and his team found themselves asking ‘‘Do other chromosomes lead to transgenerational effects? Do transgenerational effects occur in humans? What is the molecular basis for these effects?’’

If genetic variants act across generations, then traits have a genetic basis, however this study found that certain ‘disease genes’ can occur in previous generations and not necessarily in the affected individuals. Undeniably these transgenerational effects depend on the interaction between the background and epigenetic factors relating to the Y chromosome. Nadeau and his colleagues state these transgenerational genetic effects contribute to ‘missing heritability’ which could persist for generations and that these epigenetic effects can most probably be applied to humans. Thus the attributes of an individual today could depend as much on ancestral parental genetics as on the genetic variants that they inherited.

The next major step in the study of transgenerational effects is to unfold the sequence of molecular events that initiate these epigenetic changes which occur in one generation yet subsequently lead to phenotypic changes is following generations.