DNA world

Just type the word DNA and even before the wiki link you’d get to see advertisements on paternity test or some disease related diagnostic test links, may be about 8-9 years ago when scientist were just finishing up the Human Genome project (HGP), though talked about the numerous applications of this project and how it would essentially help us to better understand the pathogenesis (progression) of various diseases little did I know there will be a whole bunch of companies making money with just all this information. Welcome to the genomic era and let’s begin with the most basic concept in this field, our DNA (of course!)

DNA, which any person related to science would also address as Deoxyribonucleic acid, as I understand is this amazing molecule which is regarded as the blue print of life for all the right reasons. I really can’t scratch my head enough to come up with a better way to direct the processes involved for the existence of any organisms (Lets leave out some of the viruses and prions for now B-I) the way the current molecular machinery works. Lots of great scientist tried to find this “secret molecule of life” all the way from Friedrich Miescher who isolated the molecule, to Pauling’s attempt to discover the structure, to Rosalind Franklin‘s X-ray diffraction picture and finally published in Nature (Many graduate student’s dream publication science journal) by Watson and Crick who bagged the Nobel prize for describing the structure of this amazing molecule.

After the discovery of DNA and understanding the structure and function, the 21^st century saw the sequencing paradigm, the completion of the HGP finally uncovered the blue print of life, those 3 billion bases pairs of DNA molecule starting from Chromosome 1 to the end of 22 chromosomes plus the sex chromosome – X and Y. And this indeed became a game changer for now we have entered a new era of Personalize Medicine, which runs on the principle that every individual (even identical twins) is unique because of their genetic makeup and its interaction with the environment, and just as we all wear clothes that fit our size, the medical care be tailor made for every person. Even though it might sound very ambitious at this stage, this kind of medical revolution has already begun to sweep through! The best example where I see it becoming a big hit is in Cancer management. Cancer being the disease of the genome is a perfect area where it finds its best use. BRAC1 and BRAC2 are two important genes which are implicated in breast cancer and now are routinely use for early screening, diagnosis and this helps in determining the best treatment option for the management of this disease by coming up with a rational drug design (since every drug is specific to a particular molecular pathway involved in each cancer case… that where the personalized concept comes in). All that sounds great but only a genetic researcher would know how difficult it is to solve many of these complex riddles in the manifestation of disease.

One of the interesting things I find about the DNA is that it is composed of only 4 types of subunits called the nucleotides namely – A, G, T, and C. These 4 magical bases as we call it are arranged in unique manner, such that base A always bond with T, base G only bonds with C and vice versa (credit goes to Prof.Chargaff for the discovery). And these bases form hydrogen bonds between their respective partners, which mean that bases AAGGC will pair up with TTCCG, let’s make a note of the concept of polarity here, i.e. the way this DNA is designed by nature (or atleast what Watson and crick proposed and we believe!) is that, it consist of 2 chains of bases which are composed of A, T, G, C such that they twist around each other like 2 people madly in love that they form an antiparallel structure ( which is what DNA looks like).  These are the sense and the antisense strand, the former called as crick and the latter called as the Watson strand is used for the transcription (a process in which the information in DNA is made use of). So if I were to show this diagrammatically, it would look like this:

Let’s consider one of these strand as 3’ ---- AATTGGCGC---5’, So the other strand would automatically be 5’----TTAACCGCG----3’, paying a little attention to this sequence one would have realized the 3’ and the 5’ numbering on either end of the sequence which indicates their polarity, just as they say opposites attract the same way the 3’end of the strand will pair with the bases on the 5’ end of the opposite strand. This polarity is due to the orientation of the Phosphodiester bond linked to the 3’carbon of one strand and the 5’ carbon on the other strand… Anyways that’s just something to remember. Of course there are different forms of this DNA…. But let’s skip that part for now.

This is so cool that I can even come up with a game which goes like this…

If a bunch of oligos (a strand of these bases) were to be floating around then can you determine the color pairs?

Cheat sheet: red –blue, green-brown

The primary interest behind this molecule for me is that it stores a lot of information (genetic data) in the language of ATGC – its bases.  This information is accessed by other molecules for carrying out various processes in an organism. But if I were to start talking about how cool the DNA is, I would say ‘Replication’. This is a very important process since this stage is vulnerable to errors which give rise to mutations. DNA is capable of copying itself and form new strands, i.e. 1 DNA molecule à 2 DNA molecule. This is what happens during cell division, if new skin cells are to be produced, a single cell will replicate it’s DNA (includes  all the 23 chromosomes) and then split the cells in such a way each cell will now have equal amount of DNA in it. Thus every cell in our body except for the germ cells (includes the egg cell or the sperms) has the same genetic information (ignoring mosaic cells). 

How are Genes and DNA related?

In a way I could say that our genome basically refers to the total amount of DNA present in our cell that would include all the chromosomes. While studying genetics of human disease, many times we are particularly only interested to know the causative genes responsible for a trait (also called phenotype, which is any characteristic feature that can be observed and analyzed) of interest. So GENE is a stretch of DNA which is responsible for a trait. For example a gene called F8 is has the information for producing a protein called Coagulation factor VIII which is involved in blood clotting process. So this gene is present on X chromosome.  The gene consists of the Promoters, important for transcription downstream (information processing), the enhancers which also help in transcription, the introns and the coding regions.

Here’s a short segment of the F8 gene where the exons are represented in red and the introns lie between the exons. The promoters usually lie upstream to the start of the gene. A mutation (e.g. any deleterious base change in the red colored region here) can cause hemophilia A. The data files are huge which requires high computing capabilities to work through genetic datasets.

>hg19_knownGene_uc004fmt.3 range=chrX:154064054-154251008 5'pad=0 3'pad=0 strand=- repeatMasking=none

atcggttactGCTTAGTGCTGAGCACATCCAGTGGGTAAAGTTCCTTAAAATGCTCTGCAAAGAAATTGGGACTTTTCATTAAATCAGAAATTTTACTTTTTTCCCCTCCTGGGAGCTAAAGATATTTTAGAGAAGAATTAACCTTTTGCTTCTCCAGTTGAACATTTGTAGCAATAAGTCATGCAAATAGAGCTCTCCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATACTACCTGGGTGCAGTGGAACTGTCATGGGACTATATGCAAAGTGATCTCGGTGAGCTGCCTGTGGACGCAAGgtaaaggcatgtcctgtagggtctgatcggggccaggattgtggggatgtaagtctgcttggaggaaggtgcagacatcgggttaggatggttgtgatgctacctgggccccaaagaaacatttctgggtaaggtgtgcacacatctgtgttattagcagaaatgctaactgccaattcttttcataggtctgacctatttgttgatattttgttctgttttgtccattgcttctcttcgtcatatgctgctcctccagaatctagagactggagtagagggagggtgaagggacaaagacaaaacttccctctgcctgcccaagcttccatagagagaatcaaggcaatgaaatccaatcaatatcacacacaagtttcatgtctggttctcttgtgtgtacatgcaatgtgtgtttttataatatcttttcctactttgggtgtaaggataatatgagccttgagttcagaagcttttcgtgttttgggggttctggtgcatttaggcagagtattaaataactttatcaatattgtctatggtcatcagttgattcagatttttctacctcttcttcagtaaatattggtatattttggtctatactttcatagaaagcaatctactgtccctagatttgataatgtattggtatcaagttatgtaagagtctcctgtgattttgttaaactgttctgtgtctgtagttatattttctttttcattccttatgttgtatatgttctcttcctctcttttaaaaataatatttccaggagttttcttgattttattggtcttgtcaagaattttcttttggtttgatttatcaatctcttttttctttctgttgcatcagtttctgcttctactttcattgatttattccttccttctaatttcctttggttcattttgttgttagatttttgcttcttgagttgaatgctgaaatcatttattttatttttttgtcttctttaaatgtgtattataaagatttaaatataatacatagattgtggctgtgtaaacattaaatgtggtcatgttgtacatactttatattctttttggttctttctgtttggctccccaccctctttccacatcagtccccttctcccccacctcagctaggtaaccccagtatgataatatatattcacatacacatacacacacacaaaggttttcttggacattatttgttttataaaattgggacattatacacacatttctcactcattaacacgtactagaactctaagtcaattggtatagctttaattcattatttttattggctatataagattctatggtatggctgtatcacaatttagtcaatatgttcactttattccagtttttggctactatatcctatatcattacatactggtgcttttacttctgttgaacaaacttgcaagaggaatattaatggaacgaagggaatgtttccttctaagttttaatttccaaagaggtcagaacttttcaaacatttctaccatcgaagtatgaaaatggccttctctctgcattcacatagcgataagttttatcctgtttttaaaatttgccaattttacaggtgtagagtgatattgcatcattactttcattgtgttatttttatttctaataagttgagcatctttttaaatgcttgttggctattggatttatttgggggatttaattagtcatatgatttgcccattattctttggactctttcatttaaaaaaattatgagaacccttttattattacaaatattaactctttgtcatgtatattgcagttttccccaagatctattgtttgtctgttgactttcttataacttttaccaaaacagtttttaatttttataatcagagatatcttttctttcatatcttcagagtcggcaaggttggttaaaaatgtttcccacacctcaagattgtacgtgtaatctcccagattttcttgcaagatgtttactgtttcgctttttatatgcattgcttcaattatctgctaattacttttgtcatatggcatgagagagggatttgtctagttttatttccatccagatcaatagcctattgtgatggcaccttttgccactgatttgaatcaacacattcatcatataaagttctcatatatattagcatatatttctggattcattaggctgtttcactaatctactattatcttgctatgccagtaccatagtgatttgattacagtgagcctatgatatcttctgatatctggtgggtgaaagcaatcctcactattctttttgtacctttcttagctattcttagacactttattcttccacataaaactgttaagatatttttcaaattaaaaagatccaagccctgttgtgattctaactgcaatttcattaaactcagaccttaattttattaatgtaataaatttaaatatttttcttattacatttatctctgtgtattttataagtgtgatgctattgttaataagatagttttctcctatttccatttatgagtgcttagtaccaaatagagataagctattggtttgtgtattttcagctttttcttttgagcctgggtctcattttgtcacccaggctggagtgcagtggggtgatctcaccttactgcagcctcaacctcctggattcaagcaattctcctgtatatcagccccccaagtagctgggactacaggagcaggccaccatgcccggaaaatttttgtatat

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 Further downstream flow and processing of information from DNA finally to proteins (which are pretty much responsible for mediating all the processes in the body) is another magnificent elaborate process involving yet another amazing molecule – RNA. Stay tuned!



COPY NUMBER VARIATIONS

Are there GNOMES in our body ?

We humans are ~99.9% identical, even though each of us is so unique, it's amazing that each of us look and feel so different because of that ~0.1%  variation in our DNA. There are different kind of variations that attribute to this uniqueness, one of them is copy number variations or CNVs in short.

You'd probably know my favorite place to find definitions by now if you were following my blogs.... of course Wikipedia.. which defines CNV's as " alterations of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA." There are part of our DNA which get duplicated and some get broken or deleted.... In my imagination, a picture of this sort comes to my mind... our genome is this large text file and some techno Gnomes are deleting, inserting, inverting or copy pasting some random portion of our DNA at any point in our lives.

We all have CNV in our genome which contributes to our heterogeneity thus decreasing the likihood of us resembling each other like the clones in a star wars series...OK so we are all unique that's nice, but what about the fact that some of these CNV's are associated with diseases. Well that's the downside of the CNV's , which is why scientist are interested in them. These CNVs can either increase susceptibility or resistance to disease depending on who gets the good penny and who gets the bad penny.

There are a great number of diseases caused by these CNVs, Cancer being the most talked about in this context since it's a known fact that cancer is the disease of the genome. There are some interesting facts about CNVs like:

• They can be inherited
• They are different in different ethnic groups
• About 18% gene expression variation are attributed to CNVs ( Based on the last literature I had looked upon)
• DNA segment longer than 1 Kb when compared to reference is considered clinically significant CNV
• Some CNVs play role in Drug metabolizing genes (This is one context where the concept of personalized medicine can be talked about)
• Cancer is associated when there is a really instable gross chromosome.

The important question that would come to one's mind when they are interested about CNVs is how to detect these and find them, well the traditional cytogenetic techniques, CGH ,FISH, BAC arrays and SNP oligo arrays are used. In case you are wondering what are these.. you know where to look (Ans:Wikipedia).
 At present Microarrays are considered the gold standard way for doing any kind of experimentation concerned with CNVs. The analysis and clinical interpretation are done using some current practical threshold values. For example Gain of function ( more than adequate proteins are produced )when  > 500kb of DNA is detected  which has some implications.There are a lot of issues using the current methods, primary statistical issues and other biases. The promise of Next gen sequencing technology bring yet another hope for the CNV studies.

The whole genome sequencing paradigm continues to spark many minds and using this approach will bring in a new dimension of experimental techniques and aid the researcher to take the current knowledge to the next level.So much for the facts (that's all I could remember from the seminar I attended today).. well there is rapid progress in discovering more and more of these CNVs and assess their role so as to help scientist and doctor to come up with better ways to treat cancer patients.

METAGENOMICS!!!

It's funny at times to realise how we tend to behave as if we are a single existing entity in this entire universe, knowing that's not true. To make my point more visible, for example today I threw this used plastic cup in the regular thrash can instead of a recycable one, most of us would think it's no big deal (specially not something to blog about..jeezzz!), well if one thinks about the big picture, it might not be so trivial. That one cup could ending up in some part of the world clogging a plant or an animal. I guess the point that I am trying to bring up is that no one lives in seclusion, we are all interconnected not just with fellow members of a species but with hundreds of species around us and within us. Thus it is important for us to realise our responsibility as a member of this big biosphere where we are as important as are other member who range from less than a micron to may be a godzilla in size. And since we were the lucky ones, out of the millions of species to evolve so rapidly and become the dominating organism, it's our responsiblity to do as much as we can to make sure the world can be a better place to live.

I found Metagenomics interesting more from a philosophical point of view, probably was evident from the first part of my blog but that ends here. But as a person who identifies herself with scientific community, I am more or less going to blog about what I learnt from my course and my personal beliefs and ideas.

Wikipedia defines Metagenomics as study of  "metagenomes, genetic material recovered directly from environmental samples" (as copy and pasted!). I pictured this as a scenario where a traditional microbiologist got us from his laminar airflow hood and pulled up his sleeves and said to himself you know what we have advanced way too much in technology so why not use that to study these little guys in concert with their community, from their natural habitat. In other words there may be lot of potential in them in their natural conditions which could be discovered and applied.

In other words through centuries we have found hundred of new organisms, cultured, studied, characterized, applied and did a whole bunch of stuff with them, now we are in the 21st century, we need to think out of the box. All this time we were studying microbes in conditions created by us, but in reality the environment is no where similar to our traditional laboratory and it would mean that we would totally miss out on all those microbes which we cannot culture.16sRNA was great to classify these guys and derive phylogentic relationships, since we came to know that there are many missing pieces of the puzzle and this was due to the fact we were zooming in on microbes which we could culture.
We use traditional molecular biology, microbiology and bioinformatics knowledge and principles to explore this field. We find all those genes that nature has given these organism to may be adapt to it's environement and use them to improve the world. There is a lot to be explore here and hopefully we will find our answer and once we do that it could translate to clean eneregy in the form of biofuels, cleaning up spills and toxics in environment through bioremediation and helps in many more ways.

Will keep updating more and more as I get time.

A Reflection

The story of evolution is very intriguing, deeply researched and it never fails to disinterest me. It kinda always seem to answer the question of existance (For me atleast!). Even though it is hard for many to believe that we have evolved from a bunch of molecules dancing around each other to this really complex organism, our understanding of science tells us that. And we don't have any other well structured belief system that can be proved to come up with any other story. So coming back to the realization of existance with the context of evolution, I feel that we starting, from an unborn child to a 109 year old person are all here for a purpose. It could be anything that we know or do not know, is good or bad  it does'nt matter.. but once having realised that as members of a civilised social dominating group of this planet our effort should be directed in a constructive manner towards establishing a community where all living orgainsms can find their respective niche and live in harmony.

Ignorance can be a curse!

There are countless examples that can prove the above statement, ignorance of our rights gives goons to control us, ignorance of causation of adverse climatic conditions continue to not stop people from wasting resources, Ignorance of what teacher teaches can get us bad grades...just to cite a few. Expanding our knowledge not only helps us to save the day at times but also makes us broad minded... which is very much what this world needs! Eradicating Ignorance can take us a long way in achiving our common goal of making this world a better place.

Will keep posted.