The Manifestation Of Genetic Diversity Biology Essay

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The biological diversity has been studied traditionally at genetic and phenotypic level. The genetic diversity, however, is manifested at various levels. Such as

Chromatin organization

Secondary structure of RNA

Protein structure

Diversity of metabolites

Diversity of metabolic pathways

Logistic diversity

Diversity in networks

The comprehensive listing of variations in the above parameters is outside the scope of this article. This article attempts to provide a perspective of the manifestations of genetic diversity in biological organisms taking a few representative examples.

Chromatin organization (Ridgway and Almouzni, 2001, Mello and Almouzni, 2001)

The variation in stimulatory factors and the basic constituents of chromatin play a strong role in conferring diversity on the dynamic structure of chromatin. The core particle of nucleosome is composed of 146 base pairs of DNA wrapped 1.7 turns around a protein octamer of two each of the core histones H3, H4, H2A and H2B and is highly conserved. In contrats, the length of the linker region, varies between species and cell type. The variable linker histones are incorporated with in this region.. Thus, the total length of DNA in the nucleosome can vary from 160 to 241 base pairs in different species. The core histones, H3, H4, H2A and H2B, are highly conserved in evolution. The central domain is the most conserved region of these histones, structurally composed of the "histone fold domain" consisting of three alpha-helices separated by two loop regions. However, the N-terminal tails of each core histone are more unstructured and and variable. . The DNA accessibility and protein/protein interactions with the nucleosome are altered by the numerous post translational modifications that are proposed to modify the charge on N-terminal tail.. Linker histones associate with the linker region of DNA between two nucleosome cores and in contrast to the core histones, they are not well conserved between species..

The assembly of DNA into chromatin involves a variety of events, starting with the formation of the basic unit, the nucleosome, and finally giving rise to a complex organization of specific domains within the nucleus. This step-wise assembly is described schematically in Fig 1

· In The first step a tetramer of newly synthesized (H3-H4)2 is deposited on the DNA to form a sub-nucleosomal particle, which is followed by the addition of two H2A-H2B dimers.

This produces a nucleosomal core particle consisting of 146 base pairs of DNA wound around the histone octamer.

This core particle combines with linker DNA to form the nucleosome.

Newly synthesized histones are specifically modified (e.g.the acetylation of histone H4).

· The next step , the maturation step involves the use of ATP to establish regular spacing of the nucleosome cores to form the nucleofilament. During this step the newly incorporated histones are de-acetylated.

· Next the incorporation of linker histones is accompanied by folding of the nucleofilament into the 30nm fibre

· Ultimately , further successive folding events lead to a high level of organization and specific domains in the nucleus.

At each of the steps described above, the modification of basic constituents of the chromatin and the activity of stimulatory factors implicated in the processes of its assembly and disassembly can lead to variation in composition and activity of chromatin.

Figure 1. General steps in chromatin assembly.

Variation in basic constituents

The elementary particle can assume variations, in the first step of chromatin assembly

at the level of DNA (for example by methylation) or

at the level of histone by differential post-translational modification and the incorporation of variant forms (for example CENP-A, a variant of H3).

All of these variations are capable of introducing differences in the structure and activity of chromatin. The vast array of post-translational modifications of the histone tails (such as acetylation, phosphorylation, methylation, ubiquitination, polyADP-ribosylation), and their association with specific biological processes has led to the formul;ation of the concept known as the "histone code", that marks genomic regions. The code is "read"by other proteins or protein complexes which are capable of understanding and interpreting the profiles of specific modifications. The incorporation of histone variants may be important at specific domains of the genome: for example, CENP-A, a variant of histone H3 is associated with silent centromeric regions and macro H2A on the inactive X chromosome of female mammals. H2A-X has been shown to be involved in the formation of foci containing DNA repair factors in the regions of DNA double-strand breaks. Growing evidence exists that H2A.Z has a role in modifying chromatin structure to regulate transcription.

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Stimulatory Assembly Factors

Histone interacting factors

Histones can form complexes with acidic factors and enhance the process of histone deposition. They act as histone chaperones by facilitating the formation of nucleosome cores and are not a part of the final reaction product. These histone-interacting factors, also called chromatin-assembly factors, bind preferentially to certain histone proteins.

For example , Chromatin Assembly Factor-1 (CAF-1) interacts with newly synthesized acetylated histones H3 and H4 to preferentialy assemble chromatin during DNA replication. CAF-1 is also capable of promoting the assembly of chromatin during the repair of DNA. The assembly of specialized structures in centromeric regions, by deposition of variant histones such as CENP-A, or telomeres may be a result of the specificity and the diversity of as yet unidentified histone chaperones.

  Remodelling machines and histone-modifying enzymes

Stimulatory factors also play an important role during the chromatin maturation stage to organize and maintain a defined chromatin state. Their effects on chromatin can induce changes in conformation at the local level, i.e. at the level of the nucleosome or more globally over large chromatin domains. These factors are of two types; the first type known as chromatin remodelling machines requiring ATP for their action , and the others that act as enzymes to post-translationally modify histones.

· Chromatin remodelling machines include multi-protein complexes (SWI/SNF, ISWI, Mi2/NuRD families).The activity of the ATPase permits the complex to modify nucleosomal structure, requiring the hydrolysis of ATP. The salient feature of these chromatin remodelling factors is their large size and multiple protein subunits including the ATPase. However, there are variations in their abundance and activity.

· post-translational modifications: the "histone code" concept has been proposed to explain the diversity of chromatin activity in the nucleus and could also be used to elucidate the diversity of chromatin activity in different individuals and species.. The unstructured N-terminal histone tails extend outside the nucleosome core and are the sites for specific post-translational modifications. The most well characterized of these modifications is the acetylation of lysine residues. Acetylation is the result of a balance between two opposing activities: histone acetyl transferase (HAT) and histone deacetylation (HDAC) (e.g. HAT A, with a histone acetyltransferase activity and HDAC1, a histone deacetylase). These post translational modifications have functional relevance also as the numerous proteins that play a role in the regulation of transcription have intrinsic histone acetyltransferase activity. Similarly, histone deacetylases have been described as part of multi-protein complexes associated with repressive chromatin.

Methylation of histones is also functionally relevant. For example, Histone H3 on lysine residue 9 is modified by a histone-methyltransferase methylation modifies the interaction of H3 with heterochromatin associated proteins.

The two possible modifications (acetylation and methylation) on the same residue (lysine 9) of the N-terminal tail of H3 is a perfect demonstration of the "histone code". Thus, acetylated lysine in H3 and H4 N-terminal tail selectively interact with chromodomain present in numerous proteins having intrinsic histone acetyltransferase activity. However, H3 methylated on lysine residue 9 interact specifically with the chromodomain of an heterochromatin associated protein HP1.

Therefore, in addition to producing alterations in the overall charge of the histone tails, proposed to physically destabilize the nucleosome, modifications impart specificity to protein:protein interactions with the histones.

In a recent study by McDaniell et al. (2010) it has been shown that the variation in chromatin structure may be of considerable applied significance. It is not known that to what extent the variation in chromatin structure and transcription factor binding may influence gene expression, and thus underlie or contribute to variation in phenotype. To address this question, McDaniell et al. studied the individual-to-individual variation and differences between homologous chromosomes within the same individual (allele-specific variation) in chromatin structure and transcription factor binding in lymphoblastoid cells derived from individuals of geographically diverse ancestry. It was found that ten percent of active chromatin sites are individual-specific; a similar proportion were allele-specific. Both allele specific and individual-specific sites were commonly transmitted from parent to child, which suggested that they are heritable features of the human genome. Thus it can be concluded that heritable chromatin status and transcription factor binding differ as a result of genetic variation and may underlie phenotypic variation in humans.

RNA secondary structure

The RNA strand database lists 4666 RNA secondary structures. The numbers may increase as the analytical and computational tools for determination of RNA secondary structure make further progress. The database also lists Pseudoknots, Multibranched loops, Internal loops, Bulge loops, Hairpin loops and non-canonical base pairs as predominant secondary structures. The genetic diversity is reflected in variation of secondary structures of RNA which is of immense functional significance .

Spliceosome carries out pre-mRNA splicing , which removes intervening introns. Multiple protein isoforms are generated from gene transcripts due to alternative splicing . The spliceosome can identify a variety of exons within a given pre-mRNA which leads to alternative splicing ., splice-site selection in higher eukaryotes depends on multiple parameters such as splice-site strength, splicing regulators, the exon/intron architecture, and the process of pre-mRNA synthesis itself. RNA secondary structures have also been hypothesized to influence alternative splicing as stable RNA secondary structures that mask splice sites are expected to interfere with splice-site recognition. Using structural and functional conservation, Shepard and Hertel (2008) identified RNA structure elements within the human genome that associate with alternative splice-site selection. The correlation of secondary structure with the alternative splicing demonstrates that RNA structure formation is an important mechanism regulating gene expression and disease.

A number of processing steps including alternative splicing are influenced by the secondary structure of RNA. Since most splicing regulatory proteins bind to single-stranded RNA, the sequestration of RNA into double strands could prevent the binding of splicing regulatory proteins to RNA. In a study by Hiller et al. it was shown that the secondary structure context of experimentally influenced splicing enhancer and silencer motifs in their natural pre-mRNA context. It was found that these splicing motifs are significantly more single-stranded than controls. These findings were validated by transfection experiments, which demonstrated that the effect of enhancer or silencer motifs on exon skipping was much more pronounced in single-stranded conformation. It was also shown that the structural context of predicted splicing motifs is under selection, suggesting a general importance of secondary structures on splicing and throwing light on functional significance of diversity in RNA secondary structure.

Fig.2 Main types of RNA secondary structure

Protein structure

During evolution, protein domains undergo many changes in sequence and structure which have impact on function. Diverse factors, such as the accumulation of sequence changes, gene duplications, gene combinations etc., are seen to contribute extensively to this diversity (Heringa and Taylor, 1997, Heringa, 1998, Lynch and Conery, 2000, Orengo and Thornton 2005, Apic et al. 2001, Todd et al. 2001, ) Insertions and deletions (indels) introduce length difference between domains. into pre-existing domains. It has been shown that protein length expansions are 40-60% greater in eukaryotes as compared to prokaryotes and that such expansions correlate with the presence of introns and accretion of functional motifs which are involved in regulatory networks (Zhang ,2000). Recent studies have also shown that protein structural differences can arise as a result of incremental growth of protein variable regions. In phylogenetic reconstructions of SCOP domain families, 42% of observed insertions occur in insert regions and contribute to structural modifications (Jiang and Blouin 2007).

In an analysis of length differences in 353 multi-membered PASS2 domain superfamily alignments ( Sandhya et al. 2008)., it has been observed that 'indels' occur in all protein classes. Infact, ~60% of protein domains from all protein classes showed at least 5% length variations from their typical domain size. The length variation varied from two-three residues to over two-fold. Also, Sandhya et al. (2008) showed that some domains are flexible and permissive to length variation ('length-deviant' domains) while others are less tolerant to length changes ('length-rigid' domains). Indels in α-helical proteins were preferentially coils (~60%) and classes with mixed topologies such as α/β and α+β prefer helices and coils in indel regions (>50%). Close examination of alignments showed that such indels occur not only as extensions to pre-existing structures, but can be introduced in existing domains into the middle of the structure. The strict maintenance of the core scaffold, despite permitting large indels, suggests that indels are likely to influence the structural/functional features of the domains in which they occur. ( Sandhya et al. 2008).

Length variation in proteins has been the object of several analyses and many groups have performed in depth studies on domain and protein length variations. Pascarella and Argos (Pascarella and Argos, 1992) had also observed that ~90% of indels in proteins of sequence identity ranging from 0-20% and 40-80% were of short length (<10 residues). They also demonstrated that that loops, coils and turns are evenly targeted for insertions and deletions. Reeves and co-workers (Reeves et al. 2006), in a comprehensive examination of structural diversity in CATH domain superfamilies, have shown that a two-fold or more variation in the number of secondary structures was observed in 56% of well-populated superfamilies. Even though such insertions are discontinuous in sequence, they co-locate in three-dimensional (3-D) space to perform functional roles or generate novel interaction interfaces. Indels have also been shown to directly influence functional differences between homologous domains( Redfern et al. 2008).

Diversity of Metabolites

Investigators have sought to evaluate the contribution of metabolic diversity to differences in the trait attributes of non-domesticated species of various important crop plants such as tomato ([(Schauer et al. (2005) . Using a GC-MS methodology that allowed quantitation of over 90 metabolites including organic acids, sugars, polyols, amino acids and a limited number of secondary metabolites, profiles were generated that differentiated the fruit and leaves of tested wild species from that of a modern domesticated cultivar. The authors concluded that "...the wide metabolic variance of primary metabolites in fruits of the wild species suggests that.....boosting the levels of nutritionally important metabolites such as lysine, methionine, ascorbate and tocopherol will stand a high chance of success". The higher levels of secondary metabolites in the wild species also suggested a valuable resource for flavor and color compounds such as volatiles and carotenoids.

In a similar study designed to correlate metabolic traits with abiotic stress resistance, Semel et al. (2007) assessed the impact of water restriction on yield performance and metabolite content of the domesticated tomato variety, M82, and the F1 hybrid of its cross with the wild tomato, S. pennellii. The fruit yield and brix (soluble organic material) content of the F1 hybrid were less affected by water restriction than that of M82. This was also true of the generated metabolic profiles; whereas the drought-induced changes in the F1 hybrid were relatively less, implying tight homeostatic control, water restriction induced profound metabolic changes in M82. These changes included dramatic elevations in the levels of amino acids, TCA cycle intermediates, sugars and polyols. Increases in levels of proline, along with its biosynthetic precursor, glutamate, were consistent with its postulated stress-protective role whereas increase in levels of glycine most probably reflected accumulation of glycine betaine. The increases in the levels of branched amino acids, certain TCA metabolites, and gentobiose, were also reported.

The diversity of metabolic pathways

The genetic diversity and consequently enzymatic and metabolic diversity is reflected in the diversity of a particular metabolic pathway (such as glycolysis). The KEGG database enlists the metabolic pathways in a variety of organism thus providing a glimpse of diversity of metabolic pathways.

Diversity in logistics:

Nature provides a large variety of efficient, flexible, and robust logistic solutions to a variety of problems. It is necessary to to catalogue and analyze dynamic organization processes and principles of adaptive self-control from biological systems, The principles of modularity, self-assembly, self-organization, and decentralized coordination are utilized in a variety of ways by biological organisms. It is important to study the variation in biological genetic resources from this point of view.

Biological networks:

Large scale studies in functional genomics now show that the networks which describe the gene-regulatory systems, protein-DNA interactions, signal transduction pathways are characterized by certain statistical signatures, in particular robustness, the capacity of the network to remain functional in the face of random deletion of nodes and edges. Elucidating the relation between the topology of the networks and their statistical properties has emerged as one of the central problems in the Systems Biology. These problems are currently being addressed in terms of the evolutionary formalism. The important parameter which has emerged from these studies is the concept, network entropy - a special case of the evolutionary entropy concept. Analytical and computational studies have shown that network entropy, a quantitative measure of the rate of information flow within the network is a precise measure of the property robustness. This relation between entropy and robustness is being used to explore the relation between the structure and function of biological networks. Different biological networks may show different network entropies.