It
was on a summer’s day in the year 1822 when Johann Mendel saw the light
of day. He inherited 50% of his genes from his father Anton and 50%
from his mother Rosina. But contrary to his postulated rules, the
expression of some genes was altered in a parent-of-origin specific
manner: Depending on whether the origin of a gene copy is maternal or
parental, the gene is active or non-active. This phenomenon is called
“genetic imprinting” or “genomic imprinting” [1].
Methylation Is Key to Genetic Imprinting
Helen Course described a “parent-of-origin effect” for the first time in 1960. Experiments with mice in 1980 revealed the first proof of parent-dependent inheritance of some genes. They used nuclear transplantation in mouse embryos with either maternal or parental chromosomes. The embryos could not develop normally, despite a diploid genome [2].
Since this discovery, researchers have tried to answer questions on how imprinting is facilitated, what the evolutionary advantages are, and which diseases are correlated with imprinting. In principle, imprinting is an epigenetic process that leads to monoallelic expression without altering the DNA sequence – a process known as methylation that leads to inactivation of gene expression (see also "Lamarck's Last Laugh" ). In contrast to mutation, imprinting is reversible. During gametogenesis, the imprinting status in germ cells is erased and re-programmed according to the sex of the individual [3].
A Parental Tug-of-War
As genetic imprinting diminishes the advantages of a diploid genome, it is unclear why genetic imprinting occurs. The most favored hypothesis is the “parental conflict theory”. It states that genomic imprinting reflects the differing strategies of parents regarding the proliferation of their genes [4].
A classic example is the regulation of fetal growth in mice by imprinting of the insulin-like growth factor 2 gene (Igf2) and the receptor gene Igf2r. Igf2 is a paternally expressed growth factor that enhances fetal and placental growth when it binds to the receptor Igfr1. Therefore, paternal strategy lies in extracting more resources to improve the fitness of their offspring [2].
The maternally expressed receptor Igf2r also binds Igf2 which leads to degradation of the paternally expressed protein. This antagonistic mechanism counterbalances the paternal effect and ensures an equal distribution of nutrients among the offspring [2]. Loss of genetic imprinting in Igf2- or Igf2r-locus in mice leads to either fetal overgrowth (e.g., biallelic expression of Igf2) or reduced fetal growth.
The Shady Side of Genetic Imprinting
In humans, less than 1% of the human genome is modified by parental imprinting [4]. The majority of these genes are related to growth and neuronal development of the embryo [4]. By affecting neurodevelopmental processes, genetic imprinting influences brain function and behavior. This leads to severe dysfunctions if the non-imprinted gene copy is malfunctional.
The ubiquitin-protein ligase E3A (UBE3A), for example, is only imprinted in brain tissue where the paternal copy is silenced. This enzyme is a key player in ubiquitin-mediated protein degradation. Children with a malfunctional maternal copy suffer from Angelman’s syndrome, characterized by developmental delay, epilepsy, movement disorders, and a perpetually smiling facial expression.
Other genes located near the UBE3A locus, like the genes SNRPN and NDN, are maternally imprinted. A malfunctional paternal copy leads to Prader-Willi syndrome, characterized by intellectual delay, hypogonadism, and hypotonia [4]. The risk of some neuropsychiatric disorders such as autism spectrum disorders, schizophrenia, Tourette syndrome, and bipolar disorders has also been related to genetic imprinting [4].
It seems that genetic imprinting can influence many aspects of our lives. Further investigation will bring us a better understanding of development, pathologies, and genetic fitness. And though it contradicts with Mendel’s postulated rules, he would probably be fascinated by the strange paths evolution may take.
[1] http://www.genetics.edu.au
[2] Reik and Walter, Nat Rev Genet, 2001
[3] Philips, Lobo, Nature Edu, 2008
[4] Wilkinson et al, Nat Rev Neurosci, 2007
by Betty Jurek, PhD student AG Prüß
This article originally appeared 2014 in CNS Volume 7, Issue 3, Nature vs Nurture
Methylation Is Key to Genetic Imprinting
Helen Course described a “parent-of-origin effect” for the first time in 1960. Experiments with mice in 1980 revealed the first proof of parent-dependent inheritance of some genes. They used nuclear transplantation in mouse embryos with either maternal or parental chromosomes. The embryos could not develop normally, despite a diploid genome [2].
Since this discovery, researchers have tried to answer questions on how imprinting is facilitated, what the evolutionary advantages are, and which diseases are correlated with imprinting. In principle, imprinting is an epigenetic process that leads to monoallelic expression without altering the DNA sequence – a process known as methylation that leads to inactivation of gene expression (see also "Lamarck's Last Laugh" ). In contrast to mutation, imprinting is reversible. During gametogenesis, the imprinting status in germ cells is erased and re-programmed according to the sex of the individual [3].
Mendel’s studies with pea plants established many rules of heredity, known as
"rules or principles of Mendelian inheritance":
1. Segregation: In diploid organisms, chromosome pairs are separated into individual gametes to transmit genetic information to offspring.
2. Independent Assortment: Alleles on different chromosomes are distributed randomly to individual gametes.
3. Dominance: A dominant allele completely masks the effects of a recessive allele. A dominant allele produces the same phenotype in heterozygotes and in homozygotes.
A Parental Tug-of-War
As genetic imprinting diminishes the advantages of a diploid genome, it is unclear why genetic imprinting occurs. The most favored hypothesis is the “parental conflict theory”. It states that genomic imprinting reflects the differing strategies of parents regarding the proliferation of their genes [4].
A classic example is the regulation of fetal growth in mice by imprinting of the insulin-like growth factor 2 gene (Igf2) and the receptor gene Igf2r. Igf2 is a paternally expressed growth factor that enhances fetal and placental growth when it binds to the receptor Igfr1. Therefore, paternal strategy lies in extracting more resources to improve the fitness of their offspring [2].
The maternally expressed receptor Igf2r also binds Igf2 which leads to degradation of the paternally expressed protein. This antagonistic mechanism counterbalances the paternal effect and ensures an equal distribution of nutrients among the offspring [2]. Loss of genetic imprinting in Igf2- or Igf2r-locus in mice leads to either fetal overgrowth (e.g., biallelic expression of Igf2) or reduced fetal growth.
The Shady Side of Genetic Imprinting
In humans, less than 1% of the human genome is modified by parental imprinting [4]. The majority of these genes are related to growth and neuronal development of the embryo [4]. By affecting neurodevelopmental processes, genetic imprinting influences brain function and behavior. This leads to severe dysfunctions if the non-imprinted gene copy is malfunctional.
ACTIVATION OF IMPRINTED GENES IS ORIGIN-DEPENDENT
The ubiquitin-protein ligase E3A (UBE3A), for example, is only imprinted in brain tissue where the paternal copy is silenced. This enzyme is a key player in ubiquitin-mediated protein degradation. Children with a malfunctional maternal copy suffer from Angelman’s syndrome, characterized by developmental delay, epilepsy, movement disorders, and a perpetually smiling facial expression.
Other genes located near the UBE3A locus, like the genes SNRPN and NDN, are maternally imprinted. A malfunctional paternal copy leads to Prader-Willi syndrome, characterized by intellectual delay, hypogonadism, and hypotonia [4]. The risk of some neuropsychiatric disorders such as autism spectrum disorders, schizophrenia, Tourette syndrome, and bipolar disorders has also been related to genetic imprinting [4].
It seems that genetic imprinting can influence many aspects of our lives. Further investigation will bring us a better understanding of development, pathologies, and genetic fitness. And though it contradicts with Mendel’s postulated rules, he would probably be fascinated by the strange paths evolution may take.
[1] http://www.genetics.edu.au
[2] Reik and Walter, Nat Rev Genet, 2001
[3] Philips, Lobo, Nature Edu, 2008
[4] Wilkinson et al, Nat Rev Neurosci, 2007
by Betty Jurek, PhD student AG Prüß
This article originally appeared 2014 in CNS Volume 7, Issue 3, Nature vs Nurture
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