In normal individuals, the chromosomes get inherited from both the parents. However, in certain conditions, both the chromosomes get inherited from a single parent. The other parent fails in contributing the chromosome to the zygote. This condition is known as uniparental disomy. It results in an abnormal phenotype. The chromosomes inherited through uniparental inheritance include maternally derived or paternally derived chromosomes. The disorders associated with the uniparental disomy get detected through the uniparental disomy studies. The basic subtypes of uniparental disomy include isodisomy and heterodisomy. Many mechanisms lead to uniparental disomy. They include trisomic rescue, gamete complementation, chromosomal translocations, and others. Nondisjunction gives rise to a condition known as monosomy, leading to the formation of a diploid cell line. Sometimes, centromere misdivision also leads to an Isochromosome (a chromosome with identical long arms). These conditions include uniparental disomy. Non-disjunction in meiosis-II also creates isodisomy. Sometimes, only a portion of a genomic region gets affected. It also results in the birth of a child with no disabilities. But, it certainly affects the growth of the child and the placental health.
Most of the cases do not involve phenotypic anomalies. However, genotypic changes due to the events favoring uniparental disomy (in Meiosis-II) result in the manifestation of rare recessive disorders. The phenotypic consequences could be of two types. The first one includes the presence of duplicated autosomal recessive alleles. We know that the autosomal recessive disorder mostly manifests due to the presence of two copies of mutant alleles. For example, cystic fibrosis is an example of autosomal recessive disorder with the presence of two mutant alleles. It is an example of maternal uniparental disomy-7. The offspring receives two copies of the seventh chromosome of the mother. Thus, it follows maternal uniparental disomy. Another important contributor includes genomic imprinting. It is a kind of modification to the genomic expression. The differential modification mainly arises due to the uniparental chromosome contribution. The other parent would not contribute anything to a particular chromosome pair. It involves a reversible phenomenon. Thus, the imprint gets established during the gamete formation. The imprint gets maintained throughout the embryogenesis. Next, the imprint gets erased in the germline. Imprinting is an example of the epigenetic phenomenon, and also requires chromatin modification to some extent. An example includes X-chromosome inactivation.
Image: Uniparental diagnosis (Pedigree analysis and electrophoresis)
Prader-Willi syndrome and Angelman’s syndrome:
Inheritance of the 15th chromosome pair only from the father results in a condition known as Angelman’s syndrome. Mother cells do not contribute the 15th pair of the chromosome to the baby. The Prader-Willi syndrome arises due to the inheritance of the 15th chromosome pair from the mother. In some cases, the offspring inherits the genes normally. However, the genes inherited from any one of the parents remain silent or unexpressed. For example, in Prader-Willi syndrome, only the paternal copies of genes get expressed.
Detection of uniparental disomy:
DNA polymorphism studies majorly help in detecting the uniparental disomy. They include single nucleotide polymorphism so (SNPs), variable numbers of short sequence repeats (SSRs), a variable number of longer repeats (VNTRs), and retrotransposons. The detection of single nucleotide polymorphism and includes allelic frequencies and heterozygote frequencies. The SSRs are also known as microsatellites. They exist in more than two alleles per locus. VNTRs exhibit very high polymorphisms. It involves many alleles. Retrotransposons show diallelic systems. Examples include Alu elements and LINES.
Consider a case in which the father shows heterozygosity for two alleles say “L” and “M” respectively. The mother possesses different alleles to say “Q” and “P” respectively. However, the offspring inherited the “L” and “M” alleles. Thus, the offspring inherited both the alleles only from the father. Hence, it is an example of uniparental disomy.
Trisomic rescue:
Trisomic rescue leads to the loss of a chromosome from an initial trisomy. Initially, the fertilized ovum consists of 47 chromosomes. However, later on, during the process of cell division, the cell loses one chromosome. Thus, the trisomic state gets converted into a disomic state. However, it carries errors. Two types of errors based on the phases of the cell cycle include the meiotic and mitotic errors. The meiotic error leads to the trisomic state. The mitotic error leads to the removal of the extra chromosome. The extra chromosome gets removed through nondisjunction or anaphase lag. If the removal of the extra chromosome occurs due to nondisjunction, the consequence proves to be lethal. It results in the disomic or the tetrasomic condition. However, if the extra chromosome gets removed due to the anaphase lag, it results in a trisomic or a disomic state. But, the disomic state often accompanies mosaicism. Incidences of uniparental disomy due to trisomic rescue include 4%.
Gamete complementation:
It occurs due to cytogenetic errors. Mainly, the errors occur during meiosis. Gamete complementation occurs due to nullisomy and disomy. Coincidently, they correct each other during the fertilization and look like the normal ones. Gamete complementation studies involved experiments on mice.
Chromosomal translocation:
A segment of chromosome gets shifted to some other place. It could be either another chromosome or the same chromosome. Translocations also lead to uniparental disomy. Translocations leading to uniparental disomy mostly occur in the acrocentric chromosome. Robertsonion type of translocations mainly leads to uniparental disomy.
They include the familial type of Robertsonion translocations. First, the paternal and the maternal gametes fuse and give rise to a zygote having trisomy. Later on, it undergoes trisomic rescue and loses one extra chromosome. Thus, it leads to uniparental disomy. Other types of mechanisms leading to uniparental disomy include monosomic rescue, somatic recombination, and tumors.
References:
[1] Genomic Imprinting and Uniparental Disomy in Medicine, Eric Engel, Stylianos E. Antonarakis.
[2] Uniparental Disomy (UPD) in Clinical Genetics: A Guide for Clinicians and Patients, By Thomas Liehr.
[3] The Principles of Clinical Cytogenetics, edited by Steven L. Gersen, Martha B. Keagle.
[4] Emery's Elements of Medical Genetics E-Book: With Student Consult Online Access, by Peter D Turnpenny, Sian Ellard.
[5] Medical Genetics E-Book: With Student Consult Online Access, Lynn B. Jorde, John C. Carey, Michael J. Bamshad.
[6] Thompson & Thompson Genetics in Medicine E-Book: With Student Consult Online, by Robert L. Nussbaum, Roderick R. McInnes, Huntington F Willard.
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