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Researcher gives hard thoughts on soft inheritance

Above and beyond the gene

Organisms, including humans, all inherit DNA from generation to generation, what biologists call hard inheritance, because the nucleotide sequence of DNA is constant and only changes by rare random mutation as it is passed down the generations.

But there also is evidence, especially in plants, that non-genetic factors modifying the DNA can also be inherited. The modifications of the genetic material take the form of small chemical additions to one of the DNA bases and the alternative packaging of the DNA. These so-called epigenetic modifications are known to be important for turning genes on and off during the course of an organism's life, but their importance in controlling inheritance has been debated. Many biologists are skeptical of any form of soft inheritance, where the genetic material is not constant, believing that it is only genetic information - DNA -- that can be passed onto generations.

Now Eric Richards, Ph.D., professor of biology at Washington University in St. Louis, writing in the May issue of Nature Reviews Genetics, analyzes recent and past research in epigenetics and the history of evolution and proposes that epigenetics should be considered a form of soft inheritance, citing examples in both the plant and mammalian kingdoms.

In doing so, he evokes the pre-Darwinian evolutionist Jean-Baptiste Lamarck (1744-1829), a name that evolutionary biologists thought long ago left the stage, and Soviet agronomist T.D. Lysenko. Lamarck, and more recent neo-Lamarckian researchers, believed that the environment plays a key role in a species acquiring inherited characteristics that drive variation and evolution. Lamarck, for instance, believed that shore birds acquired their long legs by constantly stretching their legs to lift themselves out of the water and that generations later that kind of environment gave rise to birds with long legs. Neo-Lamarckian views of evolutionary change stress the importance of the environment in altering inheritance.

"When most biologists hear the name Lamarck or the term soft inheritance, the reaction is, 'Oh my God, here we go again'," Richards says. "But from a molecular biology point of view there is a mechanism to do soft inheritance, and epigenetic inheritance can be construed as a form of soft inheritance. That's all I'm saying. The really heretical thing to say is that the environment could be pushing the epigenetic information in a direction that is beneficial. This is the more extreme variation of soft inheritance that raises the hackles."

Packing DNA

Epigenetic mechanisms leave DNA sequence unaltered but can affect DNA by preventing the expression of genes. Richards cites a study that shows certain epigenetic alleles can be inherited that affect tumor suppressor genes. His own work in plants has often shown epigenetic information can be inherited. The Richards lab specializes in epigenetics, a biological field that deals with information stored "above and beyond the gene," referring to the Greek meaning of the term. A classic epigenetic mechanism is a process known as DNA methylation, a chemical modification of cytosine, one of the four chemical subunits of DNA. Without proper DNA methylation, higher organisms from plants to humans have a host of developmental problems, from dwarfing in plants to certain death in mice.

The next level of gene regulation studied in epigenetics is DNA packaging. DNA is wrapped around proteins similar to the way that thread is wrapped around a spool. Loosely wrapped DNA is more readily accessible and therefore more easily expressed than tightly wrapped DNA, allowing another mechanism for regulation of gene expression. The location of DNA within the nucleus also influences gene expression.

"Epigenetics as soft inheritance in mammals puts us on a slippery slope that many people don't want to visit," Richards says.

'Different strokes' for rat folks

Still, recent studies in mice and rats have fueled the controversy. Richards cited "a whole new world called nutritional epigenomics," where researchers are trying to influence epigenetic information by of all things diet. In a study with mice hybrids, researchers provided pregnant moms with varying levels of folate and B vitamins, to affect DNA methylation.

"The idea was : If you pump these pregnant moms up with these dietary supplements, you might be able to skew the DNA methylation patterns, and thus skew the way the mice come out at the end of the day, and it works,'" Richards says. "In this particular instance that says what you're getting fed in the womb influences your phenotype - physical and physiological attributes. "

Another study showed that early grooming and nurturing of rat pups by rat moms affects methylation of a glucocorticoid receptor gene in the hippocampus in the brain. If the pups get lots of nurturing the glucocorticoid gene gets turned on and expressed early at a critical period, providing pups the beneficial outcome to handle stress later in life. Not enough nurturing and grooming, and the gene never gets turned on. Richards says that whole mechanism appears to be the result of changes in DNA methylation associated with changes in DNA packaging.

"These studies do not demonstrate inheritance between generations, but they do show that the early nutritional environment in the mice and early behavioral environment in the rat studies can change the DNA packaging on the genome, and that that is 'remembered' in the cell divisions that make the rest of the organism, " Richards says. "But this is not from one generation to another. No one has shown that yet.

"To get to the issue of the more extreme variations of soft inheritance, it has to be determined whether the environment can induce an epigenetic change in an organism that can be inherited in subsequent generations. Certainly, nobody has shown that an epigenetically induced beneficial or adaptive change has been inherited. Mechanistically, there is no reason to discount epigenetic inheritance. The biochemical nuts and bolts are there to support it. The big questions to resolve are how many epigenetic changes are induced by the environment, what types of phenotypes result from these changes, and how many of these epigenetic changes are inherited."

Tony Fitzpatrick | EurekAlert!
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