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Topic Name: New route for heredity bypasses DNA may provide a clearer window into cell's inner workings
Category: Genetic Engineering
Research persons: Laura Landweber, Mariusz Nowacki and Vikram Vijayan
Location: Princeton University, United States
Details
A group of scientists in Princeton's Department
of Ecology and Evolutionary Biology has uncovered a new biological mechanism
that could provide a clearer window into a cell's inner workings.
What's more, this mechanism could represent an "epigenetic" pathway --
a route that bypasses an organism's normal DNA
genetic program -- for so-called Lamarckian evolution, enabling an organism to
pass on to its offspring characteristics acquired during its lifetime to improve
their chances for survival. Lamarckian evolution is the notion, for example,
that the giraffe's long neck evolved by its continually stretching higher and
higher in order to munch on the more plentiful top tree leaves and gain a better
shot at surviving.
The research also could have implications for a new method for controlling
cellular processes, such as the splicing order of DNA segments, and increasing
the understanding of natural cellular regulatory processes, such as which
segments of DNA are retained versus lost during development. The team's findings
will be published Jan. 10 in the journal Nature.
Princeton biologists Laura
Landweber, Mariusz Nowacki and Vikram Vijayan, together with other members
of the lab, wanted to decipher how the cell accomplished this work, which
required reorganizing its genome without resorting to its original genetic
program. They chose the singled-celled ciliate Oxytricha trifallax as
their testbed.
Ciliates are pond-dwelling protozoa that are ideal model systems for studying
epigenetic phenomena. While typical human cells each have one nucleus, serving
as the control center for the cell, these ciliate cells have two. One, the
active nucleus, contains the DNA needed to carry out all the non-reproductive
functions of the cell, such as metabolism. The second, the germline nucleus,
like humans' sperm and egg, is home to the DNA needed for sexual reproduction.
When two of these ciliate cells mate, the active nucleus gets destroyed, and
must somehow be reconstituted in their offspring in order for them to survive.
The germline nucleus contains abundant DNA, yet 95 percent of it is thrown away
during regeneration of a new active nucleus, in a process that compresses a
pretty big genome (one-third the size of the human genome) into a tiny fraction
of the space. This leaves only 5 percent of the organism's DNA free for encoding
functions. Yet this small hodgepodge of remaining DNA always gets correctly
chosen and then descrambled by the cell to form a new, working genome in a
process (described as "genome acrobatics") that is still not well
understood, but extremely deliberate and precise.
Landweber and her colleagues have postulated that this programmed rearrangement
of DNA fragments is guided by an existing "cache" of information in
the form of a DNA or RNA template derived from the parent's nucleus. In the
computer realm, a cache is a temporary storage site for frequently used
information to enable quick and easy access, rather than having to re-fetch or
re-create the original information from scratch every time it's needed.
"The notion of an RNA cache has been around for a while, as the idea of
solving a jigsaw puzzle by peeking at the cover of the box is always
tempting," said Landweber, associate professor of ecology and evolutionary
biology. "These cells have a genomic puzzle to solve that involves
gathering little pieces of DNA and putting them back together in a specified
order. The original idea of an RNA cache emerged in a study of plants, rather
than protozoan cells, though, but the situation in plants turned out to be
incorrect."
Through a series of experiments, the group tested out their hypothesis that DNA
or RNA
molecules were providing the missing instruction booklet needed during
development, and also tried to determine if the putative template was made of
RNA or DNA. DNA is the genetic material of most organisms, however RNA is now
known to play a diversity of important roles as well. RNA is DNA's chemical
cousin, and has a primary role in interpreting the genetic code during the
construction of proteins.
First, the researchers attempted to determine if the RNA cache idea was valid by
directing specific RNA-destroying chemicals, known as RNAi, to the cell before
fertilization. This gave encouraging results, disrupting the process of
development, and even halting DNA rearrangement in some cases.
In a second experiment, Nowacki and Yi Zhou, both postdoctoral fellows,
discovered that RNA templates did indeed exist early on in the cellular
developmental process, and were just long-lived enough to lay out a pattern for
reconstructing their main nucleus. This was soon followed by a third experiment
that "… required real chutzpah," Landweber said, "because it
meant reprogramming the cell to shuffle its own genetic material."
Nowacki, Zhou and Vijayan, a 2007 Princeton graduate in electrical engineering,
constructed both artificial RNA and DNA templates that encoded a novel,
pre-determined pattern; that is, that would take a DNA molecule of the ciliate's
consisting of, for example, pieces 1-2-3-4-5 and transpose two of the segments,
to produce the fragment 1-2-3-5-4. Injecting their synthetic templates into the
developing cell produced the anticipated results, showing that a specified RNA
template could provide a new set of rules for unscrambling the nuclear fragments
in such a way as to reconstitute a working nucleus.
"This wonderful discovery showed for the first time that RNA can provide
sequence information that guides accurate recombination of DNA, leading to
reconstruction of genes and a genome that are necessary for the organism,"
said Meng-Chao Yao, director of the Institute of Molecular Biology at Taiwan's
Academia Sinica. "It reveals that genetic information can be passed on to
following generations via RNA, in addition to DNA."
The research team believes that if this mechanism extends to mammalian cells,
then it could suggest novel ways for manipulating genes, besides those already
known through the standard methods of genetic engineering. This could lead to
possible applications for creating new gene combinations or restoring aberrant
cells to their original, healthy state.
Support for the team's research was provided by the National
Science Foundation, the National
Institutes of Health and the School of Engineering and Applied Science
senior thesis research fund.
Note for Epigenetics
Epigenetics is a term in biology used today to refer to features such as chromatin and DNA modifications that are stable over rounds of cell division but do not involve changes in the underlying DNA sequence of the organism. These epigenetic changes play a role in the process of cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.
Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
Note for Lamarckian evolution
Lamarckism or Lamarckian evolution refers to the once widely accepted idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as based on heritability of acquired characteristics or "soft inheritance"). It is named for the French biologist Jean-Baptiste Lamarck, who incorporated the action of soft inheritance into his evolutionary theories and is often incorrectly cited as the founder of soft inheritance. It proposed that individual efforts during the lifetime of the organisms were the main mechanism driving species to adaptation, as they supposedly would acquire adaptive changes and pass them on to offspring.
After publication of Charles Darwin's theory of natural selection, the importance of individual efforts in the generation of adaptation was considerably diminished. Later, Mendelian genetics supplanted the notion of inheritance of acquired traits, eventually leading to the development of the modern evolutionary synthesis, and the general abandonment of the Lamarckian theory of evolution in biology. In a wider context, soft inheritance is of use when examining the evolution of cultures and ideas, and is related to the theory of Memetics.
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