Genomic Imprinting And Assisted Reproductive Techniques Biology

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In Vitro fertilisation and Intracytoplasmic Injection are techniques that have dramatically changed the face of infertility. The first IVF baby was born in 1978 and ICSI was then introduced in 1992 for the treatment of male infertility (Paoloni-Giacobino & Chaillet, 2004). These techniques were considered to be successful substitutions for natural conception, however in recent years reports are suggesting that there may be a prevalence of birth defects in children conceived by ART (Allen & Wilson, 2006).

Although IVF and related ART procedures are generally considered safe, some studies have suggested an excess occurrence of major malformations, low birth -weight and other perinatal complications in babies conceived by ART (Halliday, 2007). Furthermore, it was recently reported that IVF and ICSI are associated with imprinting disorders in the offspring such as Beckwith- Wiedemann syndrome and Angelman Syndrome (Shiota & Yamada, 2005).

Evidence that imprinting disorders are significantly linked to ART is conflicting and somewhat preliminary however there is extensive research being carried out examine the possibility and risk of this. Many research groups are showing great interest in the field of genomic imprinting and ART which highlights the seriousness of a possible link.

It is estimated that less than 100 of the approximate 30,000 genes in the human genome may be subject to imprinting. As analysis of the Human Genome Project is completed then further information and understanding of imprinting will be generated.

(http://www.genetics.edu.au/pdf/factsheets/fs24.pdf

.What is Genomic Imprinting?

The term "Imprinting" refers to the fact that some genes, are stamped with a "memory" of the parent from whom they came: in the cells of a child it is possible to tell which chromosome copy came from the mother (maternal chromosome) and which copy was inherited by the father (paternal chromosome), this expression of the gene is called a "parent of origin effect" and was first described by Helen Crouse in 1960. Imprinted genes do not produce any product (they are inactive) depending upon whether they are transmitted to the child from the egg or sperm. It is thought that there is a mechanism whereby the gene may be "stamped" so that the expression of the inherited genetic information is modified according to whether it is passed to a child through the egg or the sperm. This modification determines whether the information contained in the gene copy is expressed or not. Genetic imprinting (or "genomic" imprinting) is the name given to this modification process.

If the gene copy is modified, it will be turned off and the cells will not produce any product from that imprinted gene copy, however this process is not a mutation. Although imprinting and a gene mutation prevent the gene from encoding the product a mutation changes the coded information in the gene permanently. The imprinting modification process is reversible in the next generation.

Genetic imprinting occurs in the ovary or testis early in the formation of the eggs and sperm. Some genes are imprinted so that they are switched off or inactive only if they are passed down through an egg cell; others will be inactivated only if they are passed down through a sperm cell. Imprinting will then occur again in the next generation when that person produces his own sperm or eggs.

(http://www.genetics.edu.au/pdf/factsheets/fs15.pdf)

Imprinting is controlled by DNA methylation and a difference in methylation between the maternal and paternal alleles (Paoloni-Giacobino & Chaillet, 2004). There are two characteristic features of imprinted genes; these are richness in CpG islands. These are genomic regions that contain a high frecuency of CpG sites. They are in and near 40% of promoters of mammalian genes (Fatemi et al, 2005). The second is the presence of clustered direct repeats near or within the CpG islands (Paoloni- Giacobino & Chaillet, 2004). DNA methylation is catalyzed by DNA methyltransferase and involves the addition of methyl units at the 5' position of cytosine residues in CpG dinucleotides (Emery & Carrell, 2006). Methylation induces changes in the chromatin structure and it is associated with silencing gene expression thus provides a way of controlling expression (Dennis, 2003).

Imprinting during development

The genome undergoes reprogramming in order to ensure that every generation receives the sex specific imprint. (Paoloni-Giacobino & Chaillet, 2004). This has been demonstrated during gametogenesis and during preimplantation development (Reik & Walter, 2001).

Imprinting patterns in sperm are modified during epididymal transit where global sperm DNA methylation is greatly reduced in preparation for fertilisation via passive demethylation and the sperm becomes hypermethylated in comparison to the oocyte (Emery and Carrell, 2006). Protamine removal occurs at fertilisation and further demethylation occurs at this stage and also through morula stage. Methyl transferase is then directed from the cytoplasm into the nucleus of the cells in the blastocyst inner cell mass where a new embryonic methylation pattern is established (Emery & Carrell, 2006).

Imprinting genes are associated with the regulation of embryonic and fetal growth, as well as placental function. Defects in genomic imprinting can occur at any stage of the reprogramming process and can have a severely detrimental outcome such as embryonic death, excess, defective or impaired fetal development (Paoloni-Giacobino & Chaillet, 2004).

Imprinting Associated Disease:

Beckwith- Wiedemann Syndrome: the symptoms of this disease are a large tongue, organs and bodysize, a small heart, umbilical hernia and neonatal hypoglycaemia. The long term outcome for children born with this syndrome are that they have an increased risk of developing embryonic tumors, including nephroblastoma and liver tumors. (Niemitz & Feinberg, 2004). The approximate frequency of this disease is 1 in 14,000 and is caused by a loss of methylation imprint (Paoloni - Giacobino & Chaillet, 2004).

Angelman Syndrome: the symptoms of this disease include mental retardation, abnormal walk, speech impairment, seizures and an overly happy demeanour. (Orstavik et al., 2003). The incidence of this disease is approximately 1 in 15,000 and is caused by imprinting defect that is a result of a deletion on a maternal chromosome (Paoloni- Giacobino & Chaillet, 2004).

Prader -Willy Syndrome: Symptoms include mental retardation, decreased muscle tone, short stature, emotionally unstable, insatiable appetite that ultimately leads to obesity. The frequency of this disease is 1 in 10,000 and is caused by a paternal deletion that leads to the same imprinting disease as Angelman Syndrome (Paoloni-Giacobino & Chaillet, 2004).

Silver- Russell Syndrome: symptoms of this disorder are numerous and include body asymmetry and low weight for height, hypoglycaemia and mental retardation. Faulty imprinting can be a cause for this syndrome (Lidegaard et al., 2005).

More generally imprinting can have an impact on neurological development and behaviour. Some disorders such as Autism, bipolar affective disorder, schizophrenia, alcohol abuse and audiogenic seizures may have links with imprinting defects (Paoloni- Giacobino & Chaillet, 2004). Also certain childhood cancers such as kidney cancers and retinoblastoma have been linked to imprinting defects. (Lidegaard et al., 2005).

Imprinting and ART

Some studies have suggested that defects in imprinting can arise from ART and have also demonstrated that singleton human IVF babies have lower birth weight and higher incidence of congenital anomalies than natural conception babies (Behr & Wang, 2004). Possible reasons for an increased rate of imprinting defects in ART could be linked to the parents in that ART patients appear to have an increased frequency of chromosomal rearrangements, also ART procedures such as ICSI and culturing may disturb epigenetic programming or the biochemistry of the embryo (Behr & Wang, 2004, Shiota & Yamada, 2005).

Studies have shown that superovulation can lead to the production of oocytes without their correct primary imprint and with methylation changes (Gardner and Lane, 2005, Sato et al., 2007). In addition to superovulation the maternal genetic and dietary status has a suggested involvement in abnormal gene expression (Gardner & Lane, 2005).

Marques et al.,((2004) have suggested that sperm from oligospermic men have increased abnormal methylation of the H19 gene which has been associated with Beckwith - Wiedmann syndrome and early childhood cancers. This group claim to have identified a pathway of methylation error that is increased in babies from assisted reproduction.

Research carried out to examine the Igf2-H19 gene region of embryonic stem cells derived from IVF blastocysts, lead the particular group to suggest that ART may cause imprinting errors that involve both aberrant DNA methylation and histone methylation at an epigenetic switch of the region (Li et al., 2005).

Several studies have demonstrated that adverse culture conditions can have effects on gene expression and imprinting (Behr & Wang, 2004). The sensitivity of the embryo to its surrounding environment has been shown to reduce as development proceeds and thus its environment has a lesser effect on gene regulation (Gardner & Lane, 2005). Another suggestion is that zygotes and embryos need to have contact with the oviduct path to elicit necessary immunity and genomic programming processes, this contact obviously does not occur in cases of ART, thus the processes of these embryos and zygotes may be abnormal as a direct cause of technology being used (Valenzuela, 2005).

Conclusion

Research has clearly demonstrated that babies born from ART are at increase risk of preterm delivery, low birth weight and some obstetric complications compared with spontaneously conceived pregnancies (Shiota and Yamada, 2005). It is unclear whether or not children born as a result of ART are at increased risk of imprinting disorders; however the risk cannot be ignored (Allen et al., 2006). Documented evidence is contradictory; however several groups have demonstrated that imprinting disorders are increased in children born from ART, especially those from oligospermic men (Emery & Carrell. 2006). Also several studies have demonstrated an increased incidence of disorders such as BWS and AS (Allen & Reardon, 2005, Li et al., 2005). Although the number of patients involved in these studies has been small, the risk is none the less highlighted (Allen & Reardon, 2005).

It is also unknown whether IVF technologies or patient infertility is the major contributor to adverse outcome. (Halliday, 2007). It has been suggested that patients with fertility problems may be predisposing their gametes and embryos to greater sensitivities through the processes of ART. These include fertility drugs, the processes of IVF, ICSI and culturing. However it may be that epigenetic alterations are associated with infertility and symptoms are subsequently revealed through ART (Gardner and Lane, 2005).

Alternatively, some research groups have said that they do not support reports of increased risk of imprinting diseases after IVF and have found no difference in the incidences of childhood cancers, mental diseases, congenital syndromes and developmental disturbances in children born as a result of natural conception and those from ART (Lidegaard et al., 2005).

In general some groups find the evidence that ART may be associated with increased incidence of imprinting disorders inconclusive and suggest that there is insufficient evidence to make such associations (Schieve et al., 2004).

Although research is somewhat conflicting, there is a general consensus that the outcome and development of children born as a result of ART must be followed and monitored closely to find out if these infertile patients and their offspring have a higher risk of suffering epigenetic errors and imprinting disorders (Barri et al., 2005). There is also a need for multi-centre large scale studies to be carried out to clarify the possible link (Allen & Reardon, 2005). The possibility of these risks also highlights the importance of adequate counselling for infertile couples prior to embarking on the ART pathway (Merlob et al., 2005)




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