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BurchGene

Biannually Magazine Issued by the Genetics and Bioengineering Department

December 2016 Volume 1 Issue 1

DNA DATA STORAGE

LUIS AND REINHARD REVEAL THEIR SECRETS: FIRSTHAND ANSWERS ABOUT DNA STORAGE

ISSN 2490-3515

SECRETS: FIRSTHAND ANSWERS ABOUT DNA STORAGE ISSN 2490-3515 Bacterial adhesion and biofilms on surfaces Do you
SECRETS: FIRSTHAND ANSWERS ABOUT DNA STORAGE ISSN 2490-3515 Bacterial adhesion and biofilms on surfaces Do you
SECRETS: FIRSTHAND ANSWERS ABOUT DNA STORAGE ISSN 2490-3515 Bacterial adhesion and biofilms on surfaces Do you
Bacterial adhesion and biofilms on surfaces Do you understand DNA structure? A biofilm is a
Bacterial adhesion and
biofilms on surfaces
Do you understand
DNA structure?
A biofilm is a structured consortium of bacteria
embedded in a self-produced polymer matrix.
DNA encodes all of the information for a cell to
reproduce, make proteins, and function properly.
You have your chance in your own blood Stem cells have the remarkable potential to
You have your chance
in your own blood
Stem cells have the remarkable potential to
develop into many different cell types.

READ ABOUT POPULAR AND INTERESTING TOPICS IN GENETICS

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Popular Topics in Genetics

FROM THE EDITORS

Dear colleagues, students, respected professors, collaborators and respected readers. The issue you are holding in your hands is the second edition of the BurchGene magazine. Strong will, clear goals and love for science drove us to continue helping, inspiring and bringing simple, accessible and fun scientific topics to our audience. As a new science magazine we are always aiming at deliver- ing fresh, intelligent coverage of hot topics in science and its comprehension to the scientists as well as to the other readers interested in genetics and bioengineering. Since the publication of the very first issue, BurchGene maga- zine has become very popular among readers. It has been seen on the streets of New York City and experienced a boom on the global networks. As a result, we have successfully recruited a great number of people to contribute to the current issue. We have talked with the associate professor of com- puter science and engineering at the University of Washington, Luis Henrique Ceze, who introduced us to the very inter- esting and new topic called “DNA as a memory storage”. Also, post-doctoral researcher at the Department of Electrical Engineering and Computer Sciences at the University of California, Reinhard Heckel, dedicated his time to answering our questions and brightening our perspectives about capaci- ty of a DNA molecule in storage and its readability. Within these pages you will also discover articles written by our respected professors and students at the Department of Genetics and Bioengineering. Biofilms, stem cell research and mtDNA diseases are only some of the attractive topics you will encounter. Last but not least, our students were kind enough to share with us two research posters. The issue is free of charge, and this decision was guided by our belief that knowledge is a right and not a privilege. This would not have been possible without our sponsors: International Burch University, Nalaz and Somnacare whom we are sincerely grateful for supporting us every step of the way.

Enjoy reading,

The Editors

“Sometimes the smallest step in the right direction ends up being the biggest step of your life” -Naeem Callaway

Burc hG e ne M a gaz in e | De ce m b er 2016

Executive editors: Ahmed Osmanović Adnan Fojnica Fatima Mrkulić Editorial board: Prof. Dr. Rifat Hadžiselimović
Executive editors:
Ahmed Osmanović
Adnan Fojnica
Fatima Mrkulić
Editorial board:
Prof. Dr. Rifat Hadžiselimović
Prof. Dr. Dragan Primorac
Prof. Dr. Damir Marjanović
Prof. Dr. Mrsada Hukić
Assoc. Prof. Dr. Amina Kurtović Kozarić
Assoc. Prof. Dr. Enisa Omanović
Assist. Prof. Dr. Almir Badnjević
Assist. Prof. Dr. Serkan Dogan
Lectors:
Monia Avdić Ibrišimović, PhD
Elma Ferić Bojić, MSc
Sabina Halilović, BSc
Graphic Design:
Ahmed Osmanović
Publisher:
International Burch University
Address:
Francuske revolucije bb, Ilidža 71210
Telephone: 033 782-130
E-mail: burch.gene.mag@ibu.edu.ba

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CONTENTS

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» p.14
» p.11
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» p.4
» p.4
» p.7 » p.16
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p.7
» p.16

4 IS DNA THE FUTURE OF DATA STORAGE?

This interesting topic discusses some of the main ideas of bioinformatics as an intersection between genetics and computer science.

6 INTERVIEW

To better understand work of scientist with DNA as a memory storage, we spoke with Luis

Ceze, an University of Washington professor and Reinhard Heckel, researcher at the Berkeley.

8 BIOFILMS

Many bacteria exist in associations known as biofilms, which are considered as complexes of microorganisms in which cells stick to each other and often adhere to a surface.

11 STEM CELL RESEARCH

Stem cells are undifferentiated cells in multicellular organisms, capable of reproduction and giving rise to indefinite number of cells of the same type, as well as other types of cells.

14 RESEARCH OF GBE DEPARTMENT

Our professors and students actively attended many conferences at which they were able to increase their scientific knowledge, awareness and expertise with which they hope to optimize the GBE approach.

16 DNA INFO GALLERY

Considering DNA as one of the most important life units, this article provides all basics one should know about this macromolecule, its basic structural components and function.

18 NUCLEAR GENES ASSOCIATED WITH MITOCHONDRIAL DISORDERS IN HUMANS

Going deeply into the pores of molecular genetics, this article discovers how correlation between mitochondrial and nuclear genome affects mitochondrial disorders.

20 mtDNA DISEASES – A STORY OF CRAFTY TRICKSTERS IN OUR CELLS

Very informative article that represents a continuation of the previous article by sharing some common ideas while focusing on specific features of mtDNA diseases.

22 POSTER 1

» p.8
» p.8

GBE staff in association with other scientists published their research titled “Prediction of Y chromosome haplogroups in human population living in Bosnia and Herzegovina”.

24 POSTER 2

The fact is that genetics and genetic predispositions play an important role in resistance and response of one individuum to a certain disease.

26 THE 9 GREATEST GENETICISTS

List of the Greatest Minds of All Time, throughout history, in the field of genetics who have

made notable contributions to genetics with photos, bios, and other information.

BurchGene Magazine | December 2016

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IS DNA THE FUTURE OF DATA STORAGE?

COMPUTATIONAL BIOLOGYTopics in Genetics IS DNA THE FUTURE OF DATA STORAGE? Layla Abdel-Ilah The DNA molecule in

Layla Abdel-Ilah

OF DATA STORAGE? COMPUTATIONAL BIOLOGY Layla Abdel-Ilah The DNA molecule in our cells carries genes which

The DNA molecule in our cells carries genes which code and produce all types of proteins and enzymes responsible for carrying out all cell functions in addition to identify organism’s physical char- acteristics. In addition, DNA mol- ecule has an important applications in forensic science, bioinformatics, molecular biology, etc. Scientists know a lot about DNA’s functions, and it is not a surprise that they can implement its great benefits in different sci- entific areas. However, the situa- tion was different when we heard that DNA would be implemented in data storage. However, using DNA mole- cules as a storage medium is not a new idea in the scientific com- munity. The general idea about the possibility of storing informa- tion on DNA molecules were orig- inally made by Mikhail Neiman and published in 1964–65 in the

Radiotekhnika journal, USSR. On August 16, 2012, research was published in the journal Science by George Church and colleagues at Harvard University, in which DNA was encoded with digital information that included an HTML draft of a 53,400 word book written by the lead researcher, eleven JPG images and one JavaScript program. Multiple copies for redundancy were added and 5.5 petabits can be stored in each cubic millimetre of DNA. This research result showed that DNA can be another type of storage medium such as hard drives and magnetic tapes. Researchers started with digital version of the book. Next, on paper, they translated the zeros into either the A or C of the DNA base pairs, and the ones into either the G or T. Then, using specific standard lab- oratory techniques, they created short strands of actual DNA that

held the coded sequence—almost 55,000 strands in all. Each strand contained a portion of the text and an address that identified the loca- tion in the flow of the book. In that form, millions or even billions copies of the book could fit easily into a test tube and, under normal conditions, last for very long years. In January of 2013, researchers from the European Bioinformatics Institute (EBI) reported an improved system in Nature at the same time as Churce and colleagues (2013). The article was submit- ted at around the same time as the paper of Church and colleagues. Over five million bits of data con- sisting of text files and audio files were successfully stored and then perfectly retrieved and reproduced with accuracy between 99.99% and 100%. The costs per mega- byte were estimated at $12,400 to encode data and $220 for retrieval. In May of 2016, PRI news

encode data and $220 for retrieval. In May of 2016, PRI news Figure 1: DNA can

Figure 1: DNA can be used as a data storage medium

Burc hG e ne M a gaz in e | De ce m b er 2016

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Our DNA molecule is very suitable for data storage purposes because it is:

1. Very small and dense: 1 kg of DNA

is enough to store all the data avail-

able in the world, we can just get a lot of information into a very small space.

2. Can last for a long years in a good

condition particularly when kept cool and dry: we can retrieve DNA from very old, hundred-thousand-year-old fossils.

3. Very interesting for us: it contains

our genetic material so we will keep searching and discovering more and more about it.

will keep searching and discovering more and more about it. Figure 3: Storing a movie onto

Figure 3: Storing a movie onto a DNA

published that Microsoft and team of researchers from University of Washington have been preparing DNA containing digital data for sequencing, which allows them to read and retrieve the original files. The team was able to store 150 kilobytes on a strand of DNA.

The DNA molecule in our living cells is very small and dense which allow us storing all the data available in the world in 1 kg of DNA. DNA, especially if kept cool and dry, has the ability to remain intact for many years, and thereby enable the retrieval of molecules that are hundreds to thousands of years old. Moreover, our genetic material is very interesting for us all the time so we will keep search- ing and discovering more and more about it.

DNA strand contains a phos- phate group, a sugar group, and a nitrogen base. There are four nitro- gen bases, namely (A)denine, (T) hymine, (G)uanine and (C)ytosine. The sequence of base is a kind of genetic code that is passed from one generation to the next one. Oligonucleotides are short DNA molecules, these small bits of nucleic acids can be synthesized in the laboratory as single strand mol- ecule with any original sequence. Storing data is an essential DNA function. In fact, much before the advent of semiconductors, DNA has been carrying genetic data for generations, but the difference is in the format of data. DNA carries data in form of sequence of nitro- gen bases, for example, GTACCG, whereas semiconductors carry data in form of binary digits, for

semiconductors carry data in form of binary digits, for Figure 2: Nitrogen bases sequence is available

Figure 2: Nitrogen bases sequence is available in form of binary number

example, 100101. Assume we want to store an image in one DNA strand. The image is broken down into pixels. The brightness value of each pixel, available in form of binary number is uniquely mapped to nitrogen bases sequence, for example, 11010 is mapped to GATCAG. Once the map is ready, DNA is artificially synthesized in a labo- ratory. Once synthesized, DNA can be stored in test tubes for a long years, hundreds or even thousands. When we wish to retrieve the data we just have to read the synthe- sized DNA using a DNA sequenc- ing techniques. This process will generate the exact sequence of base pair, which can be turned back into binary data and, in turn, the image can be regenerated. The issue is not how much data we can store, but is how to manage all that data, know what we have and where it is, and ensure that it is in a retrievable form. We are going to have to overcome all the management and administra- tive hurdles. The largest obstacle to making DNA data storage useful is the cost, because you need to store some- thing cheaper than one tape, other- wise, no one will buy it. However, that may no longer be the case in another 10 years, as technology gets cheaper and faster. Beyond that, it will only be a matter of time before you will make the decision on where to store your library of photos, books, or videos: an exter- nal hard drive, or a strand of DNA.

BurchGene Magazine | December 2016

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Popular Topics in Genetics

LUIS AND REINHARD REVEAL THEIR SECRETS ABOUT DNA STORAGE

INTERVIEWLUIS AND REINHARD REVEAL THEIR SECRETS ABOUT DNA STORAGE To better understand work of scientist with

REINHARD REVEAL THEIR SECRETS ABOUT DNA STORAGE INTERVIEW To better understand work of scientist with DNA

To better understand work of scientist with DNA as a memory storage, we spoke with Luis Henrique Ceze, an University of Washington associate professor of computer science and engineer- ing and the university’s principal researcher on the project. About starting research on DNA he said:

„I’ve had a side interested in DNA computing for a while, and while on sabbatical in 2013 I head about Nick Goldman’s work and got immediately interesting in explor- ing what a whole end-to-end would look like. At that time my collab- orators Karin Strauss and Georg Seelig also got interested and we put a research program together.“

as a binary code are used in data storage, so how can we encode them in A, T, C and G?

“First you need to break the information into units that would fit in a molecule of about 100-200 nucleotides. Then you map groups of 0s and 1s into ACGTs in a way that avoids too many repeated letters (like AAAA would be bad). This way, say a movie, would be mapped to a large collection of these molecules.”

What are main challenges in using DNA storage as a common tool in everyday life?

“DNA synthesis still needs to get much cheaper and much faster to be competitive.”

We know that 0s

and 1s

much faster to be competitive.” We know that 0s and 1s Figure 4: Luis Ceze, University

Figure 4: Luis Ceze, University of Washing- ton associate professor of computer science

It is predicted that all digital data worldwide will grow to over 16 zettabytes in 2017. Can DNA be possible solution to this problem?

Yes certainly, especially for archival storage that is not accessed very frequently.

What is current capacity of DNA molecule in storage, how much data can we store inside of it?

We estimate that we can fit about 1 exabyte (~10^18) in about 1 cubic inch.

What methods are used in storing and reading of DNA?

“DNA synthesis is used to make DNA molecules that encode information (the “write” process). DNA sequencing is used to read the composition of the molecules that are then decoded back to digital data.”

Regarding the cost and realistic expectation for com- plete data storage in DNA molecule, professor Ceze con- cluded that it would have cost about $10 million to sequence a human genome in 2007 but close to only $1,000 in 2015, so we can expect similar reduce in cost with the storage of data in DNA due to technology devel- opment. In his opinion, it would take around a decade for DNA molecule to completely substi- tute classical devices used in data storage.

Another scientist that spoke with us about DNA storage is Reinhard Heckel, Dr. sc. techn., postdoc- toral researcher at the Department of Electrical Engineering and Computer Sciences, University of California, Berkeley. He is a person that dealing with machine learning, mathematical signal pro- cessing and above all computa- tional biology. His interes in appli- cations in genomics and biology, arises from believe that there are important problems in those areas and algorithmic and statistical

Burc hG e ne M a gaz in e | De ce m b er 2016

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Popular Topics in Genetics 7 Figure 5: Reinhard Heckel, Dr. sc. techn., postdoctoral researcher at the

Figure 5: Reinhard Heckel, Dr. sc. techn., postdoctoral researcher at the Department of Electrical Engineer- ing and Computer Sciences, University of California,

Berkeley

ideas are crucial for addressing those problems.

that

Why

do

you

think

the storage of data in DNA is impressive?

“DNA is considered an attrac- tive future storage medium due to its longevity and high informa- tion density. More important for storage than its density is perhaps its longevity: As our experimen- tal results demonstrate, it is pos- sible to recover information from DNA even after thousands of years. Therefore, DNA has poten- tial applications in future long term storage.”

Can we use some other mole- cules beside DNA as a data storage system?

“In principle, yes. One of the reasons that DNA is a natural choice is that there are already technologies available that can write and read DNA.”

What is the advantage of DNA data storage over standard data storage devices?

“The main advantage over con- ventional data storage devices is its

longevity: Disks, flash, and tape in its current design cannot store information for more than say a few decades. In contrast, DNA can serve an essentially permanent storage medium, which makes it attractive for archi- val applications.”

DNA can stay stable in fossils for a long time and envi- ronmental condi- tions influences it vastly. What can we do to protect DNA from environmental stresses?

“It is essential for

DNA data storage to protect the DNA physi- cally as well as information the- oretically. My colleague Robert Grass from ETH Zurich devel- oped a technology for encapsulat- ing DNA in Silica. This technol- ogy allows to physically protect the DNA in a similar way than fossils do in nature. Additionally, we protect the information theoret- ically by adding redundancy to the information that we want to store.”

What is the current capacity of a DNA molecule in storage, and how much data can we store inside of it?

“A loose lower bound on the capacity is two bits per nucleotide. However, this capacity cannot be achieved as errors on the nucle- otide level occur and one has to account for those. Additionally, entire fragments of DNA do get lost. The capacity we achieved was 1.187 bits per nucleotide.”

The story does not end once the data is inside of the DNA. How do you read this data? Are there any difficulties with it?

“There are several technologies for reading (sequencing) DNA, we used an Illumina sequencer,

however other techniques exists and can be used. There are several difficulties with reading the DNA, the main issue is that the reading process is not error free and additionally takes time. However, a large number of reading errors are much less of a problem in DNA data storage than in biological and medical appli- cations, as we can account for those with error correcting codes. Another difficulty is that typically not all sequences are read, but again we can account for this by using error correcting codes.“

You developed a scheme to correct errors in reading data based on the Reed-Solomon Codes. Can you explain how it works?

“In a nutshell, error cor- recting codes (such as Reed- Solomon Codes) add redundancy to the data, and therefore allow to correct errors, no matter where the errors occur. To illustrate the idea one can think about the sim- plest code, which is a repetition code. Specifically, if we want to send a word, say ``DNA’’, we can simply transmit it several times, e.g., send ``DNADNADNA’’. If one error occurs, say we receive ``DNADNADNZ’’, we can still decode the original informa- tion ``DNA’’ from the corrupted message. However, a repetition code is not a good code as it adds a lot of redundancy for the number of errors that it can correct. Coding theory is about finding an optimal tradeoff between the number of errors that can be corrected and the redundancy that is added. Moreover, coding theory addresses the computationally efficient recon- struction of the information. In DNA data storage, the information is stored on several, non-connnected, strands of DNA. Errors occur in individual sequences, and additionally whole sequences get lost. We developed a code that is capable of correcting errors in single nucleotides, and additionally allows to recover entire sequences that are lost.”

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Popular Topics in Genetics

The „Gold Model“ for most microbiologi- cal examinations is the study of microorganisms in pure culture or the aqueous planktonic phase. However, the paradigm about planktonic bacterial cells does not reflect the real growth of bacteria in nature. Hence, during the last decade many studies were directed towards the understanding of bacterial growth in natural condi- tions. From these studies it is clear that many bacteria exist as part of a complex association attached to the surfaces and embedded in their own extracellular matrix. Today, such asso- ciations are more com- monly known as biofilms.

matrix. Today, such asso- ciations are more com- monly known as biofilms. Burc hG e ne

Burc hG e ne M a gaz in e | De ce m b er 2016

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Popular Topics in Genetics 9 BIOFILMS Mirsada Hukić & Monia Avdić Ibrišimović regardlessweather the material

BIOFILMS

Mirsada Hukić & Monia Avdić Ibrišimović

9 BIOFILMS Mirsada Hukić & Monia Avdić Ibrišimović regardlessweather the material is natural (plant and

regardlessweather the material is natural (plant and animal) or synthetic (medical indwelling device and industrial surface).

In humans biofilms can have a protec- tive role. For example the gut commensal flora forms biofilms which are attached to epithelial cells, making a barrier which prevents the penetration of pathogens. Dental plaque is made out of different bacterial biofilms, but the decline of teeth is a consequence of proliferation of pathogenic strains in the same. Although biofilms are ubiquitous in nature, their significance in the clinical setting is often underestimated. Today biofilms represent a severe source of infection, especially in immune-compromised individuals with indwelling medical devices (like cath- eters). This has serious clinical conse- quences and is the cause of many per- sistent and chronic infections. Thereby one should have in mind that bacteria inside a biofilm are embedded inside EPS which provides them protection from the hosts immune response as well as anti- microbial remedies. Infections caused by biofilms often have recurring symp- toms until the source of the infection is not removed surgically. In opportunis- tic pathogens, like Staphylococcus epi- dermidis, the ability to form biofilms is considered a factor of virulence and so commensal bacteria become a severe source of infection in the hospital envi- ronment. Today numerous studies con- firmed that the rates of horizontal gene transfer are elevated in biofilms com- pared to planktonic bacteria. Inside bio- films horizontal gene transfer is responsi- ble for the appearance of antibiotic resis- tance which can pass from commensal to pathogenic bacteria. It is considered that the “notorious MRSA” gained the mecA gene, which is responsible for the resis- tance to methicillin, through horizontal gene transfer.

Accordingly biofilms are considered the next great challenge for microbiol- ogists and clinicians especially taking into account their high rates of resistance towards antibiotics which makes them very difficult to treat.

antibiotics which makes them very difficult to treat. BASICS Biofilms represent associations of micro- organisms

BASICS

Biofilms represent associations of micro- organisms which are irreversibly con- nected to the surfaces by the production of a extracellular polymer substance (EPS) and at the same time show changed characteristics (phenotype), compared to the corresponding planktonic cells. EPS is a highly dehydrated and chemically complex matrix which has the aim to store nutrients and at the same time can trap other microbes as well as non-cel- lular material like minerals, crystals and corrosion products. Inside a biofilm cells function coordinately as a cooper- ative consortium, in a way mimicking a multicellular organism. The process of developing this complex and highly dif- ferentiated association from single cells demands complex genetic regulation.

The formation of biofilms occurs in several consecutive phases. In the first phase an initial transport and reversible attachment of bacteria to the surface, with adsorbed organic and inorganic nutri- ents, takes place. Subsequently EPS gets secreted and it forms bridges between individual cells, which results in the irre- versible attachment or „cementing“ of the cells to the surface. The last phase, in the formation of a biofilm, is the coloniza- tion of the surface. Bacteria, which are attached to the surface, grow and divide and by doing so create micro-colonies, which are regarded as the elemental orga- nization units of biofilms. The “primary colonizer“ secrets substances which attract other planktonic bacteria that are found in the environment (second- ary colonization). A completed biofilm has complex architecture and is made out of bacteria embedded in EPS coated micro-colonies, between which there are less dense parts of the matrix with perme- able water channels that aid in the trans- port of nutrients and waste products.

The colonization of surfaces and sub- sequent formation of biofilms is best studied in bacteria, although fungi, algae, protozoa and viruses have been isolated from biofilms in the industrial and medical setting. Biofilms can form on almost all surfaces in the environment,

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STEM CELL RESEARCH

TISSUE ENGINEERING10 Popular Topics in Genetics STEM CELL RESEARCH Mike Byrom and Adna Ćuk Regenerative medicine is

Mike Byrom and Adna Ćuk

CELL RESEARCH TISSUE ENGINEERING Mike Byrom and Adna Ćuk Regenerative medicine is a branch of tissue
Regenerative medicine is a branch of tissue engineering and molecular biology which deals with the

Regenerative medicine is a branch of tissue engineering and molecular biology which deals with the process of reparing and recovering human cells and tissue, returning them into normal state This makes them subsequently able to function properly as any normal cell never being

engineered. However, the best application of regenerative medicine could be considered from the aspect and very interesting scientific topic related to stem cells. These are cells which can be isolated from our body, then be engineered by various methods, and afterwards introduced into our body by different ways such as: injections of stem cells through cell therapy, induction of regen-eration by biologically active substances or by transplantation into organs and tissues. Beginning with some future capabilities of stem cells, then moving to their basics, their different types and also emphasizing the main differences between them; subsequently discussing embryonic and adult stem cells with the special attention to multipotent stem cells and their usage nowadays; and afterwards providing some basic steps regarding the maintenance of stem cells in laboratory conditions, this article could be considered as very informative for every reader. Finally, at the very end there are answers on the most frequently asked questions

about stem cells provided in this article.

Stem cells are one of the most important medical discoveries of our lifetime. They, as a class of medicine, have almost limitless potential to treat disease and to improve the quality of our lives. Many thousands of researchers worldwide continually work to better understand how these cells function and how we can utilize them to benefit mankind. The ability to grow your own tissue for transplant and the ability to regenerate or grow replacement organs is not just a pipe dream but an achievable goal Actually, there is an obvious need to draw atten- tion of all medical profession- als and members of our audience who are grounded in practicality and tend to be a little more skep- tical to the example of amazing development of a modern mobile phone. The “Communicator” was first introduced into modern culture in 1964 on the television show

Star Trek. It was a fictional hand held device that could communi- cate instantly over vast distances without the use of wires. The first iPhone was released only 46 years later and it shares startling similar- ity to that original fictional device. Technology is moving faster today than ever before and it is evident that the ability to repair damaged organs and replace diseased body parts will be possible and it will almost assuredly be in the lifetimes of our children.

There are different classes of stem cells. Almost everyone has heard of embryonic stem cells. These cells are classified as “plu- ripotent” which means they have the ability to form every type of tissue in the body. This ability to form all tissues gives them great potential. However there are a few problems with using them for medical treatment. These cells are

Burc hG e ne M a gaz in e | De ce m b er 2016

highly controversial for moral and ethical reasons that will not be dis- cussed here. Perhaps the biggest scientific problem is the nature of the cells themselves. These cells are responsible for producing the

themselves. These cells are responsible for producing the Figure 1: Stem cells help treat disease and

Figure 1: Stem cells help treat disease and thereby improve the lives of many

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The requirements for a successful storage of stem cells are:

* The identity of the donor must be clearly established.

* The donor must test negative for a panel of infectious diseases as outlined by the regulatory authorities in each country.

* The cells must be free of microbial contamination.

* The cells must exhibit cellular morphology and growth character- istics consistent with MSC’s.

* The final product must be functionally capable of differentiating into bone, cartilage and fat tissue.

* There must be a minimum of 800k cells present that meet the above criteria within the 21-day purification process.

entire body during embryogene- sis and can only be found during this short window of your lifetime. They are activated and deactivated by chemical signals at exact times as directed by their environment. This highly regulated environment, also called the womb, is responsi- ble for controlling the growth and function of these cells. When you take ES cells out of this regulated environment and put them into a non-regulated environment such as your knee they will grow without restriction and form tumors very similar to a cancer. This makes them unsuitable for human therapy.

There is another class of stem cells called adult stem cells. Adult stem cells can be found in differ- ent tissues of the body. They are no moral or ethical issues with obtain- ing or using them. Some types, but not all types, do have scientific issues that limit their usefulness since there is a huge number of dif- ferent types of adult stem cells each with different properties, provided is a brief description of, perhaps, the most important and interesting one. Namely, one type of adult stem cell is named Mesenchymal stem cells, abbreviated as MSC’s and are classified as “multipotent”. This means that they can form many but not all types of tissue found in the body. They are well known to be able to produce muscle, bone, cartilage, fat, liver, insulin secret- ing cells, and many other types of tissue. Each and every actually

means the same, so there is no need for one of these two words. In addi- tion to being able to produce many different types of tissues they can also be isolated and cultivated in a laboratory setting to a relatively large number without reducing their functionality. These cultivated cells DO NOT form tumors when injected into the body. This means that they can be used safely in a therapeutic setting. The ability to form many tissues when coupled with the ability to be cultivated and safely delivered makes them the most useful type of adult stem cell known. The samples that meet the storage requirements are then cryo- preserved at extremely cold tem- peratures by a very specialized process. The cells are stored at -196°C in the vapor phase of liquid nitrogen. Storing the material in the vapor phase of liquid nitrogen pre- vents the possibility of cross con- tamination between patients during storage.

One question There is one very frequently asked question: How long can the sample be stored?”. The answer is that all biologi- cal activity stops at temperatures below -135°C. Storing the mate- rial at temperatures colder than this effectively stops the aging process and keeps them in suspended ani- mation where they can remain for an indefinite period of time. We advertise that we will store samples for the lifetime of the donor and there is ample scientific evidence to support this statement. There are many documented and published cases of cells being stored for more than 50 years without any loss of functionality. Another frequently asked question is: “what happens if the electricity goes out?” The use of nitrogen instead of a mechanical freezer removes the dependency on electricity. There are no electri- cal requirements for the storage of samples because the temperature is a physical property of that element. In short, the power can go out and it will not affect the samples. Finally, there is one more not infrequently asked question about stem cells: “Why cannot people just wait until they need these cells and then obtain the material for therapy”? The reason is that stem cells age just like we age. They are exposed to pollution, toxins, and radiation from the environment and all of this reduces their usefulness. The MSC’s from a 5 year old are significantly better than the MSC’s from a 50 year old. You need these cells to be in an extremely young and pristine state for the best ther- apeutic results.

and pristine state for the best ther - apeutic results. Figure 2: Types of stem cells

Figure 2: Types of stem cells

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Popular Topics in Genetics

12 Popular Topics in Genetics Nermin Đuzić Over the last few years, prominent professors and hardworking

Nermin Đuzić

Over the last few years, prominent professors and hardworking students from Burch University participa- ted in many local and international conferences related to the field of genetics and bioengineering. These conferences contributed primarily to raising awareness of people about significance and improvement of different branches of bioengineering and their implementation in the most popular natural sciences nowa- days (i.e. medicine, biochemistry, bionics, nanotechnology, biotechnology etc.) and agricultural sector of our country as well. It is evident that they gained a lot of experience, adopted new ideas and approaches and broadened their vision and knowledge. We can say that it is a great honor to have such amazing pro- fessors and colleagues sitting next to us. The primary goal of this article is to give you a brief overview of some of the most important conferences and scientific events where our professors and students took participation. Beside many conferences held in our country, there are also some of the most important conferences in other countries like neighboring Croatia and Montenegro and also in more distant coun- tries like China and Cyprus. There is no doubt that all these conferences are increasing the rating, not only of the GBE department of our University, but also of the whole Burch family, which can be seen in the continuous development and progress. Reading this article, you will get familiar with interesting topics, famous speakers and innovative ideas that may help you in your future work and career.

ideas that may help you in your future work and career. Let’s start with “The Second
ideas that may help you in your future work and career. Let’s start with “The Second

Let’s start with “The Second Symposium of Geneticists in Bosnia and Herzegovina”, which was held on the 2nd and 3rd October 2015 in the amphitheater of Faculty of Medi- cine in Banja Luka and organized by Association of Gene- ticists in Bosnia and Herzegovina and Institute for Genetic Engineering and Biotechnology. Among many oral and also poster presentations, participation in this Symposium took 4 people from our University, Professor Dr. Mirsada Hukić, Prof. Dr. Monia Avdić-Ibrišimović and two studen- ts, Adnan Fojnica and Ahmed Osmanović, with a Review Article: CEBPA gene.

We are glad to publish and share that professor Dr. Damir Marjanović, the former head of our department and current Rector of our University was a keynote speaker at the 4th International Conference on Genomics 2015 (ICG2015), which was held in Xi’an, China from 23rd to 25th Octo- ber, where he presented his work on Forensic Genomics. The three-day conference was organized by Genetics So- ciety of China, Chinese Academy of Sciences and Xi’an Jiaotong University and was focused on “Beyond Biologi- cal and Medical Big Data”, comprising, besides Forensic Genomics, also Marine Genomics, Epigenetics and Tran- scriptional regulation and Genomics and Big Data.

Burc hG e ne M a gaz in e | De ce m b er 2016

The Second Symposium of Geneticists in Bosnia and Herzegovina

4th International Con- ference on Genomics

2015(ICG2015)

Popular Topics in Genetics

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Popular Topics in Genetics 13 From the 29th until 31st October 2015, Sarajevo was the host
Popular Topics in Genetics 13 From the 29th until 31st October 2015, Sarajevo was the host
Popular Topics in Genetics 13 From the 29th until 31st October 2015, Sarajevo was the host
Popular Topics in Genetics 13 From the 29th until 31st October 2015, Sarajevo was the host

From the 29th until 31st October 2015, Sarajevo was the host of the XXV International Conference on Infor- ma¬tion, communication and automation technologies (ICAT 2015), whose organizers had an opportunity to wel- come researchers and scientists from the whole world. In the crowded amphitheater at Faculty of Electrical Engine- ering , participation with their work “Software Package for Tracking Status of Inspection Dates and Reports of Medical Devices in Healthcare Institutions of Bosnia and Herzego- vina“ took following professors and students from our Uni- versity: Gurbeta Lejla, Badnjević Almir, Pinjo Nejra and Ljumić Fahira.

Next important event we are going to talk about is the In- ternational Congress of students and young doctors of (bio) medicine in Bosnia and Herzegovina “MEDICON”, that was held at Medical Faculty in Tuzla from the 30th October to 1st November 2015. This Congress was a great opportu- nity for students and young doctors to broaden their hori- zons and improve their knowledge in medicine and related scientific fields. Participation had been taken also by our students Ahmed Osmanović and Adnan Fojnica and their mentor Prof. Dr. Damir Marjanović with a poster-presenta- tion on the topic: Genetic predisposition to a heart disease.

Now it’s time to move on conferences from this year. First such conference worth attention is XIV Mediterra- nean Conference on Medical and Biological Engineering and Computing (MEDICON 2016), held from 31st March until 2nd April 2016 in Paphos (Cyprus). The event was organized by University of Cyprus, IFMBE and other in- stitutions. “Software Solution for Tracking Inspection Pro- cesses of Medical Devices from Legal Metrology System“ is the title of work done by two professors from our Burch University: Almir Badnjević and Lejla Gurbeta; and fol- lowing students: Sejdinović Dijana, Alić Berina and Ab- del-llah Layla.

We are proud to have an opportunity to share information that our professor doc. Dr. sci. Almir Badnjević, current head of our Department, and assistant Lejla Gurbeta were participants on the 39th international convention on infor- mation and communication technology, electronics and microelectronics (MIPRO 2016) situated in Opatija, Croa- tia from 30th May until 3rd June this year, where main ICT trends in industry, education, science and local govern- ment are presented. Joyfully, our professor Almir claimed:

As a member of the Program Committee and co-author of 3 papers, it was a big honor for me to be one of 1200 accre- dited participants from 30 countries.

XXV International Con-

ference on Information, communication and automation technolo- gies (ICAT 2015)

International Congress of students and young doctors of (bio)medici- ne in Bosnia and Herze- govina “MEDICON”

XIV Mediterranean Con- ference on Medical and

Biological Engineering

and

Computing (MEDI-

CON 2016)

39th

international con-

vention on information and communication technology, electronics and microelectronics

(MIPRO 2016)

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Popular Topics in Genetics

14 Popular Topics in Genetics The team consisted of three members from our depart - ment,
14 Popular Topics in Genetics The team consisted of three members from our depart - ment,

The team consisted of three members from our depart- ment, Prof. Dr. Damir Marjanović and Senior Teaching Assistants Larisa Bešić and Adna Ašić, took a partici- pation in International Union of Anthropological and Ethnological Sciences’s (IUAES) Inter-Congress, that was organized in Dubrovnik, Croatia, from 4th un- til 9th of May, 2016. After Prof. Marjanović’s speech about “Applied molecular anthropology: Retrospective and perspective,” our assistants presented two research works, namely “Turkish population currently residing in Sarajevo, Bosnia and Herzegovina – A synopsis of population genetics studies” and “Prediction of Y haplo- groups in Bosnian and Herzegovinian population based on 23 Y-STR loci “.

Last conference worth mentioning was held from 12th to 16th June in Bar, Montenegro and was named as the 5th Mediterranean Conference on Embedded Computing (MECO 2016). MECO 2016 provided an ideal opportu- nity for young scientists and engineers to exchange new ideas in many important technological areas. Among 115 papers submitted from 25 countries all over the world, following students took participation: Adnan Fojnica, Ahmed Osmanovic, Dijana Sejdinovic, Berina Alic, Sa- bina Halilovic, Halida Avdihodzic, and Almir Aljovic, while our professor Dr. Almir Badnjevic was invited speaker and the Chair of Editorial Committee.

International Union of Anthropological and Ethnological Sciences’s (IUAES) Inter-Congress

5th Mediterranean Conference on Embed- ded Computing (MECO 2016)

There is no doubt that these interactive conferences are great and unique opportunity not only for profes- sors, but also for students to exchange their ideas and experiences with others, to improve and raise their knowledge but also to meet new people in the same branches. Currently, students and professors are also actively participating in organizing the 2nd International Conference on Medical and Biological Engine- ering that will be held in Sarajevo in March 2017. This is exciting, informative conference with the goal of sharing ideas and best practices in biomedical engineering and related fields. Let’s recall that The 1st Conference of Medical and Biological Engineering in Bosnia and Herzegovina (CMBEBIH 2015) was successfully held from 13th to 15th March 2015 and organized by the Bosnia and Herzegovi-na Medical and Biological Engineering Society. Therefore, we are warmly inviting and suggesting you to come and experience “Pursuing innovation. Shaping the future”. This is a chance that you shouldn’t miss.

Don’t miss #cmbebih2017!

This is a chance that you shouldn’t miss. Don’t miss #cmbebih2017! Burc hG e ne M

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THANKS TO OUR SPONSORS

Popular Topics in Genetics 15 THANKS TO OUR SPONSORS SomnaCare Prvi privatni centar za poremećaje spavanja
Popular Topics in Genetics 15 THANKS TO OUR SPONSORS SomnaCare Prvi privatni centar za poremećaje spavanja
SomnaCare Prvi privatni centar za poremećaje spavanja u Bosni i Hercegovini KONTAKT Branilaca Šipa 20,
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DNA

INFO GALLERY

BurchGene Club

Popular Topics in Genetics DNA INFO GALLERY BurchGene Club DNA UNDERSTANDING G enome is the complete

DNA UNDERSTANDING

Genetics DNA INFO GALLERY BurchGene Club DNA UNDERSTANDING G enome is the complete genetic or DNA
Genetics DNA INFO GALLERY BurchGene Club DNA UNDERSTANDING G enome is the complete genetic or DNA
Genetics DNA INFO GALLERY BurchGene Club DNA UNDERSTANDING G enome is the complete genetic or DNA
Genetics DNA INFO GALLERY BurchGene Club DNA UNDERSTANDING G enome is the complete genetic or DNA

G enome is the complete genetic or DNA comple-

ment of an organism. It includes the genetic material of the nucleus and cytoplasm. All organisms have a genome made up of DNA, con- taining genes. Genomes may vary in their size, number of genes, number of chromosomes, and how genes are organized within chro- mosome(s), and the DNA may be circular or linear. A given organ- ism has only one genome regard- less of whether the organism is haploid, diploid, or polyploid. The term was originally used to denote one haploid set of chromosomes in a eukaryote organism. The genome projects are having a profound impact on health-care discoveries. The main purpose of genome proj- ects is to access the entire genome sequences that can be used to find out the probable genes and their functions in various organisms. Some important genomes that are partially or completely sequenced include that of e.coli,, yeast, arabi- dopsis, drosophila, mice, humans, rice,etc.

C hromosome is a structure composed of a very long

molecule of DNA and associ- ated proteins (e.g. histones) that carries hereditary information. Chromosomes are especially evi- dent in plant or animal cells under- going mitosis or meiosis, where each chromosome becomes con- densed into a compact, readily vis- ible thread. In nondividing cells chromosomes typically assume a more dispersed form called chro- matin. The number of chromo- somes is characteristic for the spe- cies concerned. In a bacterium only one chromosome is evident as the cell is about to divide. After DNA replication, the two new chromo- somes attach to a specialized site on the bacterial plasma membrane for segregation to the two daugh- ter cells.

membrane for segregation to the two daugh - ter cells. E ach duplicated chromosome has two
membrane for segregation to the two daugh - ter cells. E ach duplicated chromosome has two

E ach duplicated chromosome has two sister chromatids,

which are joined coppies of the original chromosome. The two chromatids, each containing an identical DNA molecule, are ini- tially attached all along their leng- hts by protein complexes called cohesins; this attachment is known as sister chromatid cohesion. Each sister chromatid has a centromere, a region of the chromosomal DNA where the chromatid is attached most closely to its sister chroma- tid. This attachment is mediated by proteins bound to the centro- meric DNA; other bound proteins condense the DNA, giving the duplicated chromosome a narrow „waist“. The portion of a chromatid to either side of the centromere is referred to as an arm of the chro- matid. Later in a cell division pro- cess, the two sister chromatids of each duplicated chromosome sepa- rate and move into the new nuclei, one forming at each end of a cell.

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Popular Topics in Genetics 17 N ucleotide is one of the struc - tural components, or

N ucleotide is one of the struc- tural components, or build-

ing blocks, of DNA and RNA. A nucleotide consists of a base (one of four chemicals: adenine, thy- mine, guanine, and cytosine) plus a molecule of sugar and one of phos- phoric acid.C, T, and U are called pyrimidines and each has a single nitrogen-containing ring. A and G are called purines and each has two nitrogen-containing rings.

called purines and each has two nitrogen-containing rings. N ucleosome a particle that forms the primary
called purines and each has two nitrogen-containing rings. N ucleosome a particle that forms the primary

N ucleosome a particle that forms the primary pack-

ing unit of DNA in chromatin. Nucleosomes give electron micro- graphs of decondensed chromatin a ‘beads-on-a-string’ appearance, and are released on mild digestion of eukaryotic nuclei with micro- coccal endonuclease. Each consists of a segment of duplex DNA, 160- 240 base pairs long, with associ- ated histone; about 146 base pairs of the DNA comprise a core par- ticle and the remainder form the linker DNA.

a core par - ticle and the remainder form the linker DNA. D NA-looping mechanisms are

D NA-looping mechanisms are part of networks that

regulate all aspects of DNA metab- olism, including transcription, rep- lication, and recombination. DNA loop formation may have different functions in different cellular con- texts; in some cases, the loop itself is requisite for regulation, while in others the increase in the effec- tive local concentration of pro- tein may account for the effects observed. The ability of DNA to form loops is affected by the dis- tance between binding sites; by the DNA sequence, which determines deformability and bendability; and by the presence of other proteins that exert an influence on the con- formation of a particular sequence.

influence on the con- formation of a particular sequence. D NA or deoxyribonucleic acid is an
influence on the con- formation of a particular sequence. D NA or deoxyribonucleic acid is an
influence on the con- formation of a particular sequence. D NA or deoxyribonucleic acid is an

D NA or deoxyribonucleic acid is an very important

molecule found in every living organism. It’s responsible for heredity – it carries, stores and express hereditary material. DNA is composed of four basic com- ponents called nucleotides. Each nucleotide is made up of phos- phate group, sugar (deoxyribose type) and one of four nitrogenous bases ( adenine, guanine, thymine, cytosine). DNA molecule is com- posed of two long chains (strands) in form of thin double felix. DNA contains the information (genes) that codes for proteins. The gene is the basic physical and functional unit of heredity.

gene is the basic physical and functional unit of heredity. T he nucleic acid bases jut
gene is the basic physical and functional unit of heredity. T he nucleic acid bases jut

T he nucleic acid bases jut out from the sugar phosphate

backbone and are free to form con- nections with other molecules. The most stable structure occurs when another single strand of nucleotides aligns with the first to form a dou- ble-stranded molecule, as seen in the DNA double helix . Each base forms hydrogen bonds to a base in the other strand. There are two types of bases in DNA: purines (guanine and adenine) and pyrim- idines (cytosine and thymine). Each base pair consists of one purine connected to a pyrimidine via hydrogen bonds. Guanine pairs only with cytosine (G-C) via three hydrogen bonds. Adenine pairs only with thymine (A-T) in DNA

or uracil (A-U) in RNA. Because an adenine-thymine (A-T) or ade- nine-uracil (A-U) base pair is held together with only two hydrogen bonds, it requires less energy to break the connection between the bases than in a G-C pair. BurchGene Magazine | December 2016

than in a G-C pair. BurchGene Magazine | December 2016 D NA eukaryotic cells is packed

D NA eukaryotic cells is packed by association with

specific proteins such as the his- tones into a structure known as chromatin. The fundamental unit of this structure is the nucleosome in which the DNA is wrapped twice around a unit of eight histone mol- ecules. This structure is compacted further into the so-called solenoid structure in genes that are not tran- scriptionally active or about to become active. The tightly packed solenoid structure can be com- pacted even further, by extensive looping, to form the chromosomes that are visible during cell division.

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Popular Topics in Genetics

NUCLEAR GENES ASSOCIATED WITH MITOCHONDRIAL DISORDERS IN HUMANS

Dževida Tarakčija

WITH MITOCHONDRIAL DISORDERS IN HUMANS Dževida Tarakčija MOLECULAR GENETICS mitochondria are responsible for mtDNA

MOLECULAR GENETICS

DISORDERS IN HUMANS Dževida Tarakčija MOLECULAR GENETICS mitochondria are responsible for mtDNA biosynthesis and

mitochondria are responsible for mtDNA biosynthesis and mainte- nance, for translation machinery of mitochondria. They are involved in mitochondrial dynamics, complex assembly, CoQ10 (coenzyme Q10) biosynthesis and indirectly affect- ing OXPHOS function.

Mitochondrial disorders

Mitochondrial disorders are regulated with mitochondrial DNA and nuclear DNA. Over the last few decades it is become obvious that correlation between mitochondrial and nuclear genome affects on mitochondrial disor- ders. Those mitochondrial dissor- ders that are caused by mutation in genes encoded in nucleus become object of attention in recent years. Different expression of OXPHOS has major impact on disease expression, because this system provides energy. Mitochondrial disorders of nuclear DNA origin primarily result from dysfunction of the mitochondrial respiratory chain (RC) or ATP synthesis. These disorders can affect one organ or more, but usually those organs depend on aerobic metabolism such as brain, heart, kidney and muscles. Mutations on structural and non-structural nuclear genes could lead to mitochondrial disorders, such as Leigh syndrome, Lactic acidosis, Encephalomyopathy, Autosomal dominant paragangli- oma, Spastic paraplegia, Cerebellar ataxia, Deafness. Table-1 sum- marize number of structural and non-structural nuclear genes that affect those disorders.

non-structural nuclear genes that affect those disorders. Figure 1: Organization of the mammalian mitochondrial genome

Figure 1: Organization of the mammalian mitochondrial genome (A) and the mitochondrial respiratory chain (B)

Mitochondria are mem- brane-bound organelles that are present in all nucleated cells. Their primary function is to produce ATP and to support aerobic respira- tion by oxidative phosphorylation (OXPHOS). Beside these func- tions, mitochondria are involved in process of apoptosis, aging, store calcium for cell activities, generate heat and mediate cell growth. Shaped like an oval, its size is 0.5 to 10uM. Furthermore, it is inherited maternally and it is unique because it has own circu- lar genome (mitochondrial-DNA) which consist of 16 569 bp and it is separated from nuclear genome. MtDNA has 37 genes and encode for 22 tRNA, 2 rRNA and 13 pro- teins (Figure 1-A). In spite of the fact that the mito- chondrial and nuclear genomes are physically separated, communica- tion between them is essential for maintenance of normal function of mitochondria. It is estimated that nuclear-encoded genes account for

99% of proteins responsible for mitochondrial energetics, morphol- ogy and redox regulation. Nuclear genes encode some mitochondrial imported proteins, including com- ponents of oxidative phosphoryla- tion complexes and factor associ- ated with replication, transcription, assembly, function and turnover. In general, nuclear genes involved in mitochondrial function can be clas- sified in two groups: structural and non-structural genes. Structural nuclear genes are involved in pro- duction of proteins that build com- plexes of OXPHOS. The respira- tory chain or oxidative phosphor- ylation system (Figure 1-B) con- sists of about 90 structural pro- teins assembled into four com- plexes (I-IV) and complex V which is ATP synthase. Seven subunits of complex I, one subunit of complex III, three subunits of complex IV and two subunits of complex V are encoded by mitochondrial proteins. Non-structural nuclear genes which are connected with

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Autosomal dominant paraganglioma

The paraganglioma (PGL) syndromes are autosomal dom- inant disorders characterized by familial predisposition to PGLs, phaeochromocytomas (PCs), renal cell cancers, gastrointesti- nal stromal tumors and, rarely, pituitary adenomas. Every disor- der is connected with transforma- tion in a gene encoding a specific subunit of succinate dehydroge- nase. Scientists have recognized four types of inherited paragangli- oma-pheochromocytoma, named types 1 through 4. Every type is recognized by its genetic cause. Individuals with types 1, 2, and 3 commonly create paragangliomas

in the head or neck area. Hereditary

paraganglioma-pheochromocy-

toma is commonly diagnosed in a man’s 30s. Symptoms of heredi- tary paraganglioma are elevations in blood pressure, headache, epi- sodic profuse sweating, irregular heartbeat, pallor, and apprehen- sion or anxiety. Paragangliomas are vascularized tumors that can be benign, malignant, functional or nonfunctional. The areas in which paraganglioma can be found is in the neck, head, pelvic areas, thoracic and abdominal area. Pheochromocytomas are catechol- amine-secreting paragangliomas found in the adrenal part and they are also known as adrenal chro- maffin tumors. Clinical features of catecholamine excess include hypertension, headache, sweat- ing, palpitation. Burnichon et al, (2009) reports that in the 2000. and 2001., genes that encode for three subunits of the succinate dehydro- genase enzyme (SDHD, SDHB and SDHC genes) have major effect for genetics of paragangli- omas and pheochromosytomas. Mutations in these genes result in changing of succinate dehydro- genase complex (complex II) of OXPHOS. Mutations which are summarized in Table-2 will result in premature stop codon, trun-

cated protein or they are in highly conserved regions. All of this will affect the function of succinate dehydrogenase complex leading to mitochondrial non-function and cause disorders. Hereditary head and neck paragangliomas

Table 1: Mitochondrial disorders correlated with mutations found in nuclear genes

disorders correlated with mutations found in nuclear genes (Figure-2) are tumors associated with nervous system and

(Figure-2) are tumors associated with nervous system and muta- tions found on genes have effect on catalytic subunits of complex

II (flavoprotein and iron protein),

SDH enzyme activity and mito- chondrial morphology.

SDH enzyme activity and mito- chondrial morphology. Figure 2: representation of paragan- glioma formed on the

Figure 2: representation of paragan- glioma formed on the neck

SDHC and SDHD encode for integral membrane-protein sub-

units. Mutations in all these genes result in neoplasia which is the formation or presence of a new, abnormal growth of tissue. SDHD is gene that encode for small subunit of cytochrome b in suc- ciate-ubiquinone oxidoreductase (complex II) while SDHC code for large subunit of cytochrome b

in succinate-ubiquinone oxidore-

ductase and they are connected to type 1 and type 2 paraganglioma

respectively. Inactivation of SDHD gene in patient with paraganglioma is associated with the complete and selective loss of complex II elec- tron transfer activity and with loss of the succinate dehydrogenase (mediated step of the Krebs cycle). Mitochondrial diseases are extremely difficult to diagnose due to extreme locus and allelic hetero- geneity, with both nuclear and mito- chondrial genes potentially respon- sible. There are different types of mutations such as insertion, dele- tion, substitution, transition that can lead to change of amino acid and result in truncated protein or complete loss of protein function. So far, a number of mitochondrial syndromes correlated with muta- tions in nuclear genes are identi- fied. Significant clinical variabil- ity in individuals that do not fit per- fectly into one particular syndrome further complicates the diagnosis. More research with focus on iden- tification of nDNA and ntDNA mutations that are associated with particular mitochondrial disorder and development of specific diag- nostic assays are required. The era of massively parallel sequencing promises a faster pace of discov- ering genes involved in mitochon- drial biogenesis.

Table 2: Mutation found in sturctual and non-structural nuclear genes correlated with autosomal dominant paraganglioma

and non-structural nuclear genes correlated with autosomal dominant paraganglioma BurchGene Magazine | December 2016

BurchGene Magazine | December 2016

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mtDNA DISEASES – A STORY OF CRAFTY TRICKSTERS IN OUR CELLS

mtDNA DISEASES – A STORY OF CRAFTY TRICKSTERS IN OUR CELLS HUMAN GENETICS Jasin Hodžić Interest

HUMAN GENETICS

Jasin Hodžić

CRAFTY TRICKSTERS IN OUR CELLS HUMAN GENETICS Jasin Hodžić Interest in mitochondria and their genome has

Interest in mitochondria and their genome has blossomed over the last few decades. As the gath- ered knowledge expanded, the dis- eases caused by mitochondrial dys- functions have become an important area of human pathology. Human mitochondrial DNA (mtDNA) is a small gene-rich, circular mole- cule of 16,569 bp. Besides the 13 components of oxidative phosphor- ylation, mtDNA encodes 2 ribo- somal RNAs and 22 tRNAs. Those rRNAs and tRNAs are necessary for the synthesis of 13 polypeptides in mitochondria and therefore crit- ical for oxidative phosphorylation process. In this article we will take a look at rRNA and tRNA muta- tions of mtDNA associated with mitochondrial disease so far, and we will try to provide a compre- hensive overview of the research and materials published on this topic, and discuss the future direc- tion of the research in this area. We will begin with outlining the pecu- liarities of mitochondrial genetics and mtDNA – a humble molecule,

but a crafty trickster.

Mitochondrial DNA – a loop with a twist

In evolutionary sense, mito- chondria are generally consid- ered to be remains of ancient bac- terial symbionts, and as such they are thought to have transferred the majority of their genome to the host cell over time, facilitating creation of all contemporarily known nucle- ated eukaryotic cells (Margulis, 1971). All that has remained is a compact, app. 16,569 bp long, dou- ble-stranded, circular DNA whose complete sequence was fully elu- cidated in 1981 and further revised in 1999 (Tuppen et al., 2010). In a single eukaryotic cell, several hundreds or thousands of copies of the mitochondrial genome are present at any given time. A sit- uation known as homoplasmy prevails if all mtDNA molecules present within a cell are identical. However, the presence of two or more mitochondrial genomes in

the presence of two or more mitochondrial genomes in Figure 1: Human mitochondrial DNA map a

Figure 1: Human mitochondrial DNA map

a cell is not an excludable situa-

tion, and such case is defined as heteroplasmy. Human mtDNA is strictly inherited uniparentally, through the maternal lineage, and contains only 37 genes. These genes encode 13 polypeptides which are all core subunits of respiratory chain com- plexes I, III, IV, and V, as well as the RNA necessary for mtDNA translation: 2 rRNAs (12S and 16S) and 22 tRNAs. Schematic over- view of the structure of mtDNA is shown on the Figure 1 below. Human mtDNA genes contain no introns and almost no intergenic noncoding nucleotides, except the 1.1 kb displacement loop (D-loop), which contains transcriptional pro- moters, as well as at least one of the proposed replication origins (OH) (Figure 1).

Specific features of mtDNA diseases

There is a number of features which govern the clinical symp- toms onset, phenotypic variability, and variable penetrance of mito- chondrial diseases. These features

include the threshold effect, mitotic segregation, clonal expansion, and

a genetic bottleneck.

(1) Threshold effect: Whilst some deleterious mtDNA muta- tions are homoplasmic, the vast majority of such mutations are found in some and not all genomes. In cases of heteroplasmy, the onset of clinical symptoms is determined by the ratio of wild-type to mutant

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mtDNA. Biochemical defects and tissue dysfunction become apparent only after the necessary minimum critical proportion of mutated mtDNAs is present. The value of threshold is typically in the range of 60%–90% mutant to wild-type mtDNA. (2) Mitotic (vegetative) seg- regation: Mitochondria are ran- domly segregated during mitosis. The proportion of mutant mtDNA in the daughter cells can thus shift in heteroplasmic cells. In cases of mutant load exceeding the patho- genic threshold for that tissue, clin- ical expression of the disease can occur, as discussed in the previous section, and shown in Figure 2. (3) Clonal expansion: Clonal expansion is defined as the pref- erential amplification of mtDNA mutations to a high level in post-mitotic tissues. Such expan- sion is considered to be a result of random genetic drift, dependent on relaxed replication of the mito- chondrial genome (Elson et al., 2001), as can be seen on Figure 2. (4) Genetic bottleneck of mtDNA: Heteroplasmic mtDNA genotypes in mammals rapidly seg- regate between generations. This phenomenon, along with a return to homoplasmy in some progeny, strongly suggests the existence of an mtDNA bottleneck during development (Tuppen et al., 2010). The exact mechanism by which this genetic bottleneck occurs is cur- rently subject of fierce debates. A prevalent hypothesis states that this bottleneck arises during embryonic development, and that it is driven by a marked reduction in mtDNA copy number in the germ line (Cree et al., 2008). One of the key features of

germ line (Cree et al., 2008). One of the key features of Figure 2: Schematic overview

Figure 2: Schematic overview of mitochon- drial mitotic (vegetative) segregation and relaxed replication phenomena.

(vegetative) segregation and relaxed replication phenomena. Figure 3: Genotype to phenotype correlations in certain

Figure 3: Genotype to phenotype correlations in certain human mitochondrial diseases

clinical syndromes associated with mtDNA mutations is their extreme variability. Furthermore, they can manifest at any stage in life of patients. The age of onset reflects the level of mutation and the sever- ity of the biochemical defect on the whole. However, other factors (such as nuclear genetic and envi- ronmental factors) also have an effect on the expression of disease (Tuppen et al., 2010).

Current compendium of poly- morphisms and mutations in human mitochondrial genome is found in a database called MITOMAP. The main purpose of this database is to report published and unpub- lished data on variation of human mtDNA, and variant tables cur- rently (April 24, 2016) maintained by the database report frequen- cies from 30,589 human mtDNA sequences (MITOMAP, 2016). We used these variant tables as the key reference for presenting the rRNA and tRNA mutations of mtDNA associated with mito- chondrial disease. However, we focused primarily on confirmed associations between clinical phe- notypes and mtDNA mutations, using MITOMAP entry “Clinical Phenotypes Associated with mtDNA rRNA & tRNA Mutations, Non-LHON” (which you can access from http://www.mitomap. org/foswiki/bin/view/MITOMAP/

ClinicalPhenotypesRNA#107).

When it comes to rRNA muta- tions of mtDNA associated with clinical phenotypes, only two cor- relations are listed as confirmed in

aforementioned entry, while there is a significantly larger number of tRNA mutations mentioned (Figure

3). Great expectations – or not…?

The mutation rate of mtDNA is extremely high and it is estimated that it is 10- to 17-fold higher than the mutation rate of nuclear genome (Tuppen et al., 2010). MtDNA repair systems, although present, are not sufficient to coun- teract the oxidative damage sus- tained by the mtDNA because of its proximity to the respiratory chain complexes in the inner mitochon- drial membrane and the reactive oxygen species (ROS) they create. Furthermore, no protective histones are present whatsoever. Most alter- ations of mtDNA are neutral poly- morphisms, which have proved to be a powerful mean of tracking human migrations. The first patho- genic mtDNA mutations were dis- covered in 1988. Over 250 patho- genic mtDNA mutations (point mutations and rearrangements) have been characterized since then (Tuppen et al, 2010). These have been shown to cause a wide variety of diseases with a variable age of onset and heterogeneity of pheno- types. Disappointingly, we pres- ently have no effective therapies or cures available for patients with mtDNA disease, although a few exciting and promising experimen- tal approaches for mtDNA disease treatment are currently being inves- tigated. It is still uncertain whether they will make their way into the clinic in the near future.

BurchGene Magazine | December 2016

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Popular Topics in Genetics

T H E

9

G R E AT E S T

GENETICISTS

Berina Alić & Halida Avdihodžić

LIST OF THE TOP WELL-KNOWNAT E S T GENETICISTS Berina Alić & Halida Avdihodžić 2 Chromosomes Friedrich Miescher 1 8

Alić & Halida Avdihodžić LIST OF THE TOP WELL-KNOWN 2 Chromosomes Friedrich Miescher 1 8 6
Alić & Halida Avdihodžić LIST OF THE TOP WELL-KNOWN 2 Chromosomes Friedrich Miescher 1 8 6

2

Alić & Halida Avdihodžić LIST OF THE TOP WELL-KNOWN 2 Chromosomes Friedrich Miescher 1 8 6
Alić & Halida Avdihodžić LIST OF THE TOP WELL-KNOWN 2 Chromosomes Friedrich Miescher 1 8 6

Chromosomes

Friedrich Miescher

1 8 6 5 -

(1844)

in

H e r e d i t y

Units

Transmitted

Swiss physician and biologist, Johannes Friedrich Miescher was the first researcher to isolate and identify nucleic acid. Despite his shyness and hearing handicap, Miescher was an excellent student who initially wanted to be a priest, but his father opposed the idea and Miescher entered medical school. In 1869, while working under Ernst Hoppe-Seyler at the University of Tübingen, Miescher discovered a substance containing both phos- phorus and nitrogen in the nuclei of white blood cells found in pus. The substance, first named nuclein became known as nucleic acid after 1874, when Miescher separated it into protein and acid components. This substance is now known as deoxyribonucleic acid (DNA).

This substance is now known as deoxyribonucleic acid (DNA). 1 3 1911- Gregor Mendel (1822) Oswald
1
1
3
3

1911-

Gregor Mendel (1822)

Oswald Avery (1877)

C a r r y

G e n e s

Gregor Mendel, also knowns as the ‘the father of genetics’ was born in Heizendorf, Austria. This Austrian monk began to research the transmission of hereditary traits in plant hybrids in his monastery’s garden. His love of garden peas due to their many distinct varieties, impacted cre- ation of a seismic shift in biologi- cal thinking when he came up with the laws of inheritance. Mendel’s experiments showed that the inher- itance of certain traits in pea plants follows particular patterns. This observation became the foundation of modern genetics and the study of hereditary.

Oswald Avery was born on October 21, 1877, in Halifax, Canada. After graduating from Colgate University, he accepted a research position at the Rockefeller Institute Hospital. In 1944, he and his coworkers discovered that DNA carries a cell’s genetic material and can be altered through transfor- mation. Although many scientists acknowledge the impact of Avery’s work on the field of molecular biol- ogy, Oswald Avery did not win a Nobel Prize. The reason might be that Avery never publicly stated that a gene is made of DNA. He died on February 20, 1955.

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Popular Topics in Genetics

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Francis Crick (1916) & 6 1972-FirstrecombinantDNA James Watson (1928) 4 1952- Erwin Chargaff (1905) Genes
Francis Crick (1916) &
6
1972-FirstrecombinantDNA
James Watson (1928)
4 1952-
Erwin Chargaff (1905)
Genes
Are
Made
of
DNA
In 1944 Chargaff began his inves-
tigations into the composition of
DNA. By 1950 he had experimen-
tally determined and published cer-
tain crucial facts that led directly
to the correct elucidation of its
molecular structure. In particular,
he demonstrated three rules, now
known as Chargaff’s Rules, which
state organisms that in DNA the
ratio of the nucleic acid bases ade-
nine to thymine was roughly equal,
and that the ratio of cytosine to
guanine was also roughly equal.
His work laid the foundations for
Crick and Watson’s discoveries.
Francis Harry Compton
Crick was born on 8 June 1916
near Northampton. James Dewey
Watson was born on 6 April 1928
in Chicago and studied at the
universities of Chicago, Indiana
and Copenhagen. In 1951 in
Cambridge, Crick and Watson
started to work together. They
worked together on studying the
structure of DNA. In February 28,
they determined that the structure
of DNA was a double-helix poly-
mer, each containing a long chain
of monomer nucleotides, wound
around each other. This was one of
the most significant scientific dis-
coveries of the 20th century and
they won the 1962 Nobel Prize in
Medicine for discovery.
8 Alec Jeffreys (1950)
Professor Sir Alec John
Jeffreys was born on 9 January
1950 in Oxford, England. He is
a British geneticist, who devel-
oped techniques for DNA finger-
printing and DNA profiling. These
methods are used in forensic sci-
ence to assist police detective
work and to resolve paternity and
immigration disputes. After he fin-
ished his doctorate, he moved
to the University of Amsterdam,
where he worked on mammalian
genes as a research fellow. After
that he moved to the University of
Leicester in 1977, where in 1984
he discovered a method of show-
ing variations between individuals’
DNA, inventing and developing
genetic fingerprinting.
7 1
9
7
5
-
D
N
A
Herbert Boyer (1936)
9 2 0 0 3 -
James Thomson (1958)
C o m p l e t i o n
5 Rosalind Frenklin (1920)
o f
t h e
H u m a n
British chemist Rosalind
Franklin earned a phD in phys-
ical chemistry from Cambridge
University. She is best known
for her role in the discovery of
the structure of DNA, and for her
pioneering use of X-ray diffrac-
tion techniques applied to DNA
fibers. ‘Dark lady of DNA’ made
some photographs that provided
key insights into DNA structure,
which helped Watson and Crick
to develop DNA model who took
credit for the discovery. Franklin
died of ovarian cancer at age 37.
Herbert Wayne “Herb”
Boyer was born on 10 July 1936.
He is a researcher and entrepreneur
in biotechnology. He discovered
that genes from bacteria could be
combined with genes from eukary-
otes when he was a Professor of
Biochemistry at the University of
California, San Francisco. Also,
he discovered a method to coax
bacteria into producing foreign
proteins and by that started the
field of genetic engineering. He
received the 1990 National Medal
of Science.
James Alexander Thomson was
born on 20 December 1958. He is
an American developmental biol-
ogist best known for deriving the
first human embryonic stem cell
(SC) line in 1998. Also he is known
for deriving human induced plu-
ripotent stem (iPS) cells in 2007.
Thomson’s Lab in 1988, was the
first to report the successful iso-
lation of human embryonic stem
cells. Thomson’s group in 2007
reported a method for converting
human skin cells into cells that very
closely resemble human embryonic

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