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Male-Biased Nature of Boule and Application of Computer-Aided Drug Design

BY: Shivani Sharma | Category: Bioinformatics | Submitted: 2012-12-06 12:24:42
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Article Summary: "Boule gene is unleashing new insights into male contraception and child birth. Information on CAD Drug designing in male contraceptive pills. The function of boule though seems to be conserved but is found to be divergent in fish Medaka which shows the expression of boule in both ovaries and sperms thus raising the question if t.."


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The function of boule though seems to be conserved but is found to be divergent in fish Medaka which shows the expression of boule in both ovaries and sperms thus raising the question if the function and expression of boule is conserved too or has diverged despite the presence of highly conserved RRM sequence. To resolve this dilemma, two species from deuterostome were chosen viz. purple sea urchin (S. Purpuratus) and chicken (G. Gallus). The homologs of boule were found to be present in both the species; though the chicken DAZL exhibited its expression both in ovaries and eggs, the chicken boule homolog limited its expression only to testis. Similarly in sea urchin, a primitive deuterostome species, boule homolog was found to be testis-specific and didn't express itself in any non-gonadal tissue. However, a transcript with a complete RRM domain present in low levels was detected in ovaries but it didn't appear to be functional at all. These findings thus suggested the male biased function of boule gene and its expression limited to gonadal tissues.

Boule - Unleashing new insights into male contraception and child birth
From the yet conducted studies, it can be concluded that if and how the boule gene is important for male fertility. As it doesn't contribute to any other functions in the body, neither is important or involved in the growth and female fertility factors and processes. The infertility thus can be considered to be resulting from either of the two factors-

• The complete knock-out or deletion of the boule gene/homolog, or,
• A disruption in its highly conserved consensus sequence such as in its deeply conserved RNA binding motif domain which is located at the N terminal of boule.

The second possibility has been fully experimentally conducted and observed and was found to yield useful results. The experiments conducted with mouse boule gene showed that the boule is only associated with and required for male fertility and doesn't in any way effects female fertility. The absence, deletion or mutation results into lack of sperm production and leads to infertile males with potential to reproduce. However this doesn't effect a male's ability to copulate in any way, neither does interrogates the viability and growth of the male in question. The male is as normal as any other male of the species and continues to grow, only the sperm production is restricted while not affecting any other characters & organs.

Though the first possibility has been practically realised too, there is another application of the discovery of boule gene that can be done through gene knock-in techniques. As it is very well known that a gene can be knocked into the genome of an organism by applying suitable techniques, several experiments have been conducted on mouse for knocking in few genes and then observing the results. It is to do with the infertile males, those who are unable to produce sperms or have a low sperm count. The boule gene can be knocked in to raise the sperm count from a few or zero to the desired amount, thus bringing back a male to fertility again. Though no experiments have been conducted yet, further research in gene knock-in approach may help gaining back the sperm production and fertility in infertile males. Various cases have come into light where a couple is unable to give birth to a child due to low or no sperm count of the male partner. Therefore, by practically bringing these approaches into application, most of the problems related to child-birth and control can be resolved.

The discovery of boule gene and its homologs and their presence throughout the bilateral phyla in metazoans have remarked a significant achievement in the history of genomics and evolution and is likely to contribute further in the studies and development of theories relating to human reproductive system. The work done by Shah C, VanGompel MJW, Naeem V, Chen Y, Lee T, et al. (2010) confirms all the findings.

As the disruption of a gene or a mutation in it, effects only its own function and doesn't in any way reflect its consequences on other genes and their functions, tissues, bodily organs etc., similarly the disruption or deletion in boule homolog disrupt its own function only. By utilising these findings, more effective male contraceptive pills can be designed that would be specific to their target that is the boule gene. By directly targeting the boule gene, its function will be disrupted more effectively and thus the contraceptive issues can be resolved. It can be done either by the two methods viz. permanently deleting the boule gene for the lifelong contraception or temporarily disrupting the expression and function of boule for the time-being leading to child birth control and a remarkable approach for male contraception.

CAD Drug designing in male contraceptive pills
Computer-aided drug design is basically involved with designing of new potential drugs for the targeted disease or disease causing bioactive molecule with the help of computer aided tools. As is already pointed out, the gene boule belongs to the DAZ gene family and yields a boule protein which has significant relationship with male fertility. By using computer-aided or structure-based drug designing, this protein can be disrupted from exhibiting its functions. This can be done either by choosing a (ligand) molecule directly from the naturally existing molecules to bind perfectly to the boule protein or can be designed manually so that it binds with the maximum binding affinity to the boule, thus deactivating it.

Binding of a protein with ligand with lowest activation energy and highest binding energy causes conformational changes within the protein and the ligand/enzyme. If the protein is in an inactivated state, it gets activated and if it's already active, it gets deactivated. Deactivation of a protein usually results into loss of its function or to be more precise, a deactivated protein doesn't expresses its function. There are specific sites located throughout the 3D structure of protein known as active sites and they are where the ligand molecules binds to. It must bind with maximum affinity to the protein molecule or else the purpose won't be achieved that is the deactivation of the protein. Though no research or studies are in progress currently in regard to CAD drug designing pertaining to this specific point, but new strategies for male contraception can be expected to come out sooner or later as the CAD drug designing is evolving further and further and very rapidly.
Thus it can be concluded that the boule gene protein can be disrupted from exhibiting its function either genetically by gene knock-out techniques or by designing specific pills or to be clear, drugs by CAD, both ultimately contributing to new alternatives for male contraception. Also, the gene can be knocked in too in the infertile males to enable them to produce sperm or raise their sperm count, though the question is how. No researches have been made in that direction yet. As the gene is directly related to male fertility, further researches can lead to the production of more effective techniques to directly target the desired protein and practically achieving the dream of more effective contraceptive pills for men, thus playing an important role in child birth and its control.

About Author / Additional Info:
A Budding biotechnologist + writer from India.. Visit http://in.linkedin.com/pub/shivani-sharma/4b/91b/384 for more details .. For E-mail refer cv.napping@gmail.com
Researcher ID- J-4200-2012

References:
1. Shah C et al. (2010), Widespread Presence of Human BOULE Homologs among Animals

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