22 November 2008
| The Evolution And Significance Of Imprinted Genes |
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| Science - Genetics & Genome | |||
| Written by TS-Si News Service | |||
| Tuesday, 24 June 2008 17:00 | |||
  Epigenetics & Epigenomics. Traditional genetics attributes human characteristics to a simple arithmetical combination of inheritable traits from unchanging genes. As a result, genetic mutations and recombinations have driven most descriptions of how traits are handed down from one generation to another.
The discovery and understanding of DNA, and the role of non-coding (junk) DNA, reveals a more complex — and subtle — situation. Today, scientists know that heritable changes in gene function can occur without a change in the DNA sequence. Called epigenetics, this insight has further changed the way researchers think about heredity. Epigenetics bridges the gap between nature and nurture.
Both epigenetics and epigenomics — the genomewide distribution of epigenetic changes — are related to many other topics requiring a thorough understanding of all aspects of genetics. The latter includes aging, agriculture, cloning, evolution, sexual differentiation, species conservation, stem cells, and synthetic biology.
There are more than 200 different cell types in the human body; each cell contains the same genetic information and can, in theory, synthesize the same proteins. However, each cell type is unique and synthesizes a specific set of proteins. Nerve cells synthesize proteins that are necessary for generating nerve cells, muscle cells synthesize those necessary for building muscle fibers, etc.
This specialization takes place during early embryonic development and continues throughout a person's life. Cells exercise control over their own development using a mechanism called epigenetic regulation, which “opens” or "closes" the DNA structure. Differences in protein synthesis result from the activation and inactivation of genes.
This is fundamental to all animals, humans, and plants (eukaryotic cells). It is involved in tissue regeneration and the preservation of stem cells and DNA.
Epigenetic processes are natural and essential to many organism functions, but disruptions can result in major adverse health and behavioral effects. Variations in epigenetic gene activity regulation are causally connected in human beings to disruptions in early embryonic development and serious diseases.
The cell has to condense two meters of DNA inside a 1/100 millimeter diameter body. During the condensation process, the cell mechanism determines which genes activate. A special group of proteins, called the histones, plays a central part during this process.
The DNA is wound around the histones — which also determine the DNA structure — during condensation. They attach a number of complex and relatively unknown combinations of small chemical modifications under the influence of different enzymes. This opens and closes parts of the DNA structure to regulate gene activation — specific for each of our distinct cell types.
Imprinted genes don't rely on the traditional laws of Mendelian genetics, which describe the inheritance of traits as either dominant or recessive. In Mendelian genetics, both parental copies are equally likely to contribute to the outcome. The impact of an imprinted gene copy, however, depends only on which parent it was inherited from. For some imprinted genes, the cell only uses the copy from the mother to make proteins, and for others only that from the father.
In the mid 1980s, scientists studying mice discovered that normal development requires the inheritance of genetic material from both a male and a female. The resulting variances changed, depending on the material's origin.
One hypothesis has it that imprinting regulates embryonic growth. Maternally-expressed imprinted genes usually suppress growth, while those from the male parent usually enhance growth, ensuring continuation of the father's genes.
This is important for a species in which a single litter of offspring can result from the contributions of more than one male. However, the mother, interested in her own health maintenance (biologically speaking), "fights" the paternal genes and limits the size of the embryo or fetus. The standard human genome contains 46 chromosomes: 23 from the mother and 23 from the father. The general human pattern consists of two copies of every gene (excluding some irregularity in the sex chromosomes). Which parent contributes a specific chromosome has no effect on the expression of the genes found there. Imprinted expression can vary between tissues, developmental stages, and even species.
The Evolution of the DLK1-DIO3 Imprinted Domain in Mammals. Carol A. Edwards, et al. PLoS Biology 6(6) e135 doi: 10.1371 / journal.pbio.0060135. [ Download PDF ]
The evolution of imprinting: chromosomal mapping of orthologues of mammalian imprinted domains in monotreme and marsupial mammals. Carol A. Edwards, et al. BMC Evolutionary Biology 2007, 7:157. doi: 10.1186 / 1471-2148-7-157.
[ Download PDF ] [ Supplement PDF ]
Exceptions to the rule are caused by a phenomenon in which specific genes are expressed in a parent-of-origin-specific manner. Called genomic imprinting, or modification of DNA, it is a form of gene expression influenced by which parent supplied the gene.
And the phenomenon doesn't seem to have originated in association with sex chromosomes. Genomic imprinting evolved in mammals with the advent of live birth. The expression of genes of one parent over the other is now better understood through studying representatives of the existing lineages of mammals: the platypus and marsupial wallaby. Genomic imprinting is an inheritance process unknown to classical Mendelian inheritance. [N1] The imprinting process is one in which specific genes on chromosomes that have been inherited from one parent are expressed in an organism, while the same genes on the chromosome inherited from the other parent are repressed. That is, imprinted genes are either expressed only from an allele inherited from either the mother or the father.
From the father, expressed imprinted genes tend to promote growth while the mother's contribution suppresses it. Paternally expressed genes enhance the extraction of a mother's nutrients during pregnancy, but the maternal genome seeks to limit it.
 Dr. Anne C Ferguson-Smith, Reader in Developmental Genetics, Department of Anatomy, University of Cambridge.
A new paper in PLoS Biology investigates the evolution of genomic imprinting in a specific region of the mammalian genome [C1].
The work by Anne Ferguson-Smith, and colleagues in the UK and Australia, shows that different regions became imprinted at different times during mammalian evolution. Imprinting arises from some kind of epigenetic memory — modifications to the DNA from one parent, such as the way the chromosomal material is packaged, that do not allow particular genes to be expressed [Cf. sidebar].
The reasons why imprinting evolved with the advent of live birth have not been clearly understood. However, it is known that different patterns of imprinting occur in different classes of mammals, with some classes of mammals exhibiting the phenomenon and others that do not.
A group from the the University of Cambridge tested these ideas by mapping known sequences of imprinted genes in two mammals, the monotreme platypus and the marsupial wallaby, which occupy distinct positions in mammalian evolution.
The conflicting interests of mother and father can lead to dominance by one at the expense of the other, or even a standoff where neither succeeds. Imprinted genes are targets for numerous human difficulties because because a single genomic (or epigenomic) change can disrupt their function and cause potentially disastrous health effects. Imprinting anomalies often manifest as developmental and neurological disorders when they occur during early development, and as cancer when altered later in life.
Genetic conflicts can lead to a variety of imprinting disorders. For example,
• the lack of paternal imprinting for a copy of gene 15q11 will result in Prader-Willi syndrome (hypotonia, obesity, and hypogonadism)
• if neither copy has maternal imprinting, the result is Angelman syndrome (epilepsy, tremors, and a perpetually smiling facial expression).
Other conditions under investigation include Alzheimer disease, autism, bipolar disorder, diabetes, male sexual orientation, obesity, and schizophrenia. Cancer research has identified cancers of the bladder, breast, cervical, colorectal, esophageal, hepatocellular, lung, mesothelioma, ovarian, prostate, testicular, and leukemia, among others.
More positively, in some conditions where two parents contribute to producing young together, each parent benefits evolutionarily by coercing the other into investing more in the baby. The investment will benefit their own genes (in the form of their child) and cost an individual that is genetically unrelated — the mate.
Therefore, genes in the father may benefit from producing a placenta that demands a lot of maternal resources, and thus there would be a selection pressure to modify sperm — but not eggs — so that the genes they carry are expressed in a way that builds a demanding placenta.
Indeed, in mammals, imprinting seems to have arisen in line with the evolution of the placenta and the new work by Ferguson-Smith et al. supports this insight.
Because the evolutionary relationship between mammals is well documented, patterns of imprinting in the different genomes can provide important clues about the evolution of imprinting. There are three existing lineages of mammals:
When comparing these three mammalian groups at a specific region of the genome (called Dlk1-Dio3), Ferguson-Smith et al. found that imprinting occurred only in placental mammals.
This finding contrasts with previous work, which has found regions imprinted in both marsupials and placentals, but not in monotremes. Thus, together with previous work published in BMC Evolutionary Biology [C2], Ferguson-Smith et al. have shown that imprinting of the mammalian genome occurred gradually. Some genes became differentially expressed before the marsupial-placental common ancestor and others afterwards.
That different regions changed at different times suggests that these changes were in response to selection pressures and therefore are adaptive — beneficial to survival/reproductive fitness rather than a by-product of another process.
Interestingly, the genetic comparisons Ferguson-Smith and colleagues have made show that imprinting correlates with highly repetitive regions of DNA. In marsupials, the Dlk1-Dio3 region is double the length found in placental mammals, due to random insertion of non-coding DNA, whereas in the different placental lineages, the region has very little non-coding sequence,
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| Last Updated on Tuesday, 24 June 2008 07:46 |
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