An Overview on Chromosomal Fragile Sites in Domestic Animals
The term ‘Chromosomal fragile sites’ (CFSs) was coined in 1970 to describe recurrent chromosome breaks on the long arm of chromosome 16 (Magenis et al., 1970). A chromosomal fragile site is a specific heritable point on a chromosome that tends to form gaps and breaks on metaphase chromosomes following partial inhibition of DNA synthesis. They are chromosomal sites showing susceptibility to breakages and discontinuities in specific conditions of cell culture and also following induction with chemical substances. Chromosomal fragile sites are specific loci in the DNA that are susceptible to forming gaps or breaks under replication stress. These regions are of particular interest in understanding chromosomal instability, genetic disorders, and potential implications for health and reproduction. In domestic animals, the study of chromosomal fragile sites provides insights into the genetic diversity, breeding practices, and susceptibility to genetic abnormalities. This overview delves into the significance, characteristics, and implications of chromosomal fragile sites in various domestic animal species.
Fragile sites and reproduction
Chromosomal fragility is considered to play a key role in karyotype evolution, chromosomal rearrangements and disease etiology related to productive and reproductive efficiency of farm animals. The fragility of chromosomes and their relation with chromosome rearrangements were carried out in many livestock species. Extensive studies have been undertaken on the fragile sites (non-random chromosomal breaks/gaps) in several species of Bovidae regarding different methods of induction, and their clinical and biological significance (Riggs and Ronne, 2009). In result, bovine chromosome fragility (mainly chromosome X) was revealed to be associated with pathologies (baldy calf syndrome, dwarfism) and fertility impairment (repeat breeders, long calving interval and abortions).
Reports of CFSs in Livestock:
- Orthologs of human CFSs have been found in the syntenic regions of a number of other mammalian species, including other primates, cat, dog, pig, horse, cow, Indian mole rat, deer mouse, and laboratory mouse.
- · Ali et al. (2008) studied the dynamics of spontaneous and FUdR-inducible fragile sites in sheep (Ovis aries).
- · Prasanthi et al. (2006) showed that fragile sites can lead to various kinds of chromosomal rearrangements, which can reduce fertility.
- · Llambi and Nunez (2007) described fragile sites associated with mental retardation syndrome, parakeratosis, baldy calf syndrome, low fertility and other hereditary defects affecting human and domestic animals.
Inductions of fragile sites
Fragile sites are specific loci that appear as constrictions, gaps, or breaks on chromosomes from cells exposed to partial inhibition of DNA replication.
Agents involved in the CFSs induction
- Carcinogens, · Antibiotics, · Genotoxins, · Iinsecticides, · Irradiation · Inhibitors of DNA replication · Cytotoxic inducing agents such as FUdR, methotrexate or thymidine · Hoechst 33258 · Aphidicolin (APH) inducible fragile sites have been detected in the chromosomes of cattle, buffalo, horse and pigs. Nicolae et al. (2009) reported significant increases of Sister Chromatid Exchanges (SCEs) in the females of river buffalo with chromosome fragility expressed by many gaps, breaks and fragments. The common fragile sites were only weakly induced by conditions of thymidylate stress, which induced the fragile X and other folatesensitive fragile sites. Conversely, aphidicolin, a specific inhibitor of DNA polymerase, strongly induces the common fragile sites but only weakly induces the fragile X. The expression of all fragile sites is enhanced in particular cell types by post treatment with caffeine or theophylline. Thus, the common and rare fragile sites share some similarities but also exhibit some differences in their modes of induction. All fragile sites appear similar at the cytological level. Aside from the fragile X, which is associated with one form of mental retardation, the biological role or significance of fragile sites is unknown. However, on the basis of correlation of breakpoints, suggestions have been made that fragile sites might be playing a role in generation of non-random chromosome rearrangements. Recent advancements in sequencing and mapping of domestic animal genomes provide tools for molecular characterization of fragile sites in animal chromosomes.
Characteristics of Chromosomal Fragile Sites
- Replication Stress Sensitivity
Chromosomal fragile sites are prone to breakage or gaps during DNA replication, especially under conditions of replication stress. This sensitivity is often attributed to a slower or delayed progression of replication forks in these specific genomic regions.
- Variable Expression
The expression of chromosomal fragile sites can vary among individuals and even within different tissues of the same individual. Factors such as age, environmental stressors, and genetic predisposition can influence the degree of fragility.
- Location on Chromosomes
Chromosomal fragile sites are typically located in specific regions of chromosomes. Common fragile sites (CFS) are those that are conserved among individuals of the same species, while rare fragile sites may be unique to certain individuals or breeds.
- Association with Genetic Disorders
In some cases, chromosomal fragile sites are associated with genetic disorders and diseases. Breakage in these regions can lead to chromosomal rearrangements, deletions, or duplications, potentially causing developmental abnormalities or contributing to hereditary conditions.
Significance in Domestic Animal Species
- Genetic Diversity and Breeding Programs
Understanding chromosomal fragile sites contributes to the assessment of genetic diversity within domestic animal populations. Breeding programs can benefit from this knowledge by avoiding matings that may increase the risk of producing offspring with chromosomal abnormalities.
- Reproductive Health
Chromosomal fragility can impact reproductive health in domestic animals. Individuals with higher fragility may experience reduced fertility, higher rates of miscarriage, or an increased likelihood of producing offspring with congenital abnormalities.
- Impact on Production Traits
Chromosomal fragility may also influence production traits in livestock. Animals with increased chromosomal instability might exhibit variations in growth, milk production, or other economically important traits.
- Diagnostic Applications
The study of chromosomal fragile sites has diagnostic applications in veterinary medicine. Chromosomal analysis, including the identification of fragile sites, can be employed to assess the genetic health of individual animals or breeding populations.
Research and Technological Advances
- Molecular Techniques
Advancements in molecular techniques, such as fluorescence in situ hybridization (FISH) and genomic sequencing, have facilitated the identification and characterization of chromosomal fragile sites. These techniques enable researchers to map fragile sites to specific genomic regions.
- Genome Editing and CRISPR-Cas9
The advent of genome editing technologies, including CRISPR-Cas9, provides opportunities to investigate the functional consequences of manipulating chromosomal fragile sites. This may contribute to a deeper understanding of the mechanisms underlying fragility and potential avenues for intervention.
- Comparative Genomics
Comparative genomics allows researchers to explore the conservation of chromosomal fragile sites across different species. Understanding similarities and differences in fragility patterns contributes to broader insights into the evolution of genomic stability.
Conclusion
Chromosomal fragile sites in domestic animals represent a fascinating aspect of genomic research with implications for genetic health, breeding programs, and overall population management. As technological capabilities advance, researchers can delve deeper into the molecular mechanisms governing chromosomal fragility, potentially paving the way for targeted interventions to mitigate the risks associated with these vulnerable genomic regions. The integration of this knowledge into breeding strategies and veterinary diagnostics holds promise for enhancing the health, welfare, and genetic resilience of domestic animal populations.
The domestic animals with reduced fertility or infertility, particularly those not exhibiting any type of chromosomal aberrations should be monitored for the fragility of chromosomes. The data generated in the future will help to validate the association of fragile sites with reproductive failure in different breeds and species of domestic animals.
Compiled & Shared by- This paper is a compilation of groupwork provided by the
Team, LITD (Livestock Institute of Training & Development)
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Reference-On Request.
