Discovery of Telomeres

In 2009 Elizabeth Blackburn together with Carol Greider and Jack Szostak were awarded Nobel Prize in Physiology and Medicine for the discovery of telomeres and the enzyme called telomerase. This is probably the most important recent discovery made in biology because it makes our conception of replication much clear and it completely changed peoples view on aging and mortality. This discovery can now be found in all cell biology textbooks, and I am also studying this currently.

Telomeres are the kind of “caps” at the ends of chromosomes which protect chromosomes in the cells from fusing with each other and from rearranging. If those abnormalities occur then cancer can be developed.

Like all the chromosomes with its genes, telomeres are the sequences of DNA. A chemical code made of four nucleic acids G (guanine), A (adenine), T (thymine), C (cytosine). Blackburn studied Tetrahymena (a freshwater pond), and identified a sequence of DNA that was repeated a few times at the end tips of the chromosomes. The purpose of this identified sequence (CCCCAA) was unclear at the beginning.

Bright fluorescent staining makes telomeric regions visible (light blue tips) on these blue-stained human chromosomes.

Figure 1.

Then she found that it is essential for DNA replication (copying of it). During replication an enzyme called DNA polymerase which duplicates DNA cannot complete duplication all the way to the end of chromosome. Therefore, it was considered that telomeres become shorted and shorted after each replication and when telomere consumed the cell dies. You can think about it like the plastic end tip of the shoelace, when it is broken the shoelace tip becomes sticky and hard to tie.

Then, she noticed that something was adding a new DNA at the ends of the chromosomes. The telomeres were not shortening, and so the cells were able to replicate enormously. They were in a fact “immortal”. This something was found to be telomerase, an enzyme also called telomere terminal transferase. This enzyme adds more repeat sequences to the end of the DNA in germline cells (egg and sperm), thus making them “immortal”. However, somatic cells are “mortal” because of much lower levels of this enzyme activity. When telomeres in somatic cell shorten to critical level, this cell no longer divides. This phenomenon contributes to some of the changes we see in aging.

Here is the video where Elizabeth Blackburn explaining how she made this discovery.

Now, why actually telomeres shorten? This process is called “end replication problem” that occur in eukaryotes (with nucleus) during replication. It is like someone painting flour in a closed room and while he reaches the corner, he cannot paint the corner as he is standing there.

Take a look at this picture.

Figure 2.

When DNA is unzipped and replicates it makes two new strands: leading (5’ to 3’) and lagging (3’ to 5’) strands. The 5' and 3' indicate the carbon numbers in the DNA's sugar backbone made of deoxyribose linked with phosphate groups via phosphodiester bond. The 5' carbon is attached to phosphate group and 3' carbon is attached to hydroxyl group. Because of this DNA has directionality, like DNA polymerase catalyzes addition of nucleotides to 3’ or it only works in 5’ to 3’ end direction.

Leading strand is called so because it is synthesized continuously toward the direction of replication. Lagging strand is called so because it is synthesized discontinuously in short segments called Okazaki fragments. Each Okazaki fragment is synthesized backward the direction of replication, because DNA polymerase can only elongate strand from a free 3' hydroxyl group. This is called backstitching mechanism. There are RNA primers which provide 3'-OH groups at regular intervals along the lagging strand. While leading strand can synthesize new DNA all the way to the end, lagging strand stays short at the end. Even if last one RNA primer was built at the very end of the DNA, it cannot be removed by DNA because there is no 3'-OH group to start synthesizing it. So, DNA’s shorten. This can be clearly seen from this diagram.

Figure 3.

This “end replication problem” is solved by our enzyme telomerase. Telomerase recognizes the telomere tip of repeat sequence. Telomerase have RNA template inside and using it, telomerase elongates the parental strand by adding additional nucleotides. Therefore, the lagging strand is copied completely. Information at the ends of chromosomes is fully conveyed to the new DNA.
Working principle of telomerase can be seen from this picture and video:

Biology is developing so fast today and it is wonderful how such tiny things make such huge breakthroughs in understanding our life.

Reference list:

"Are Telomeres The Key To Aging And Cancer?." Are Telomeres The Key To Aging And Cancer?. http://learn.genetics.utah.edu/content/chromosomes/telomeres/ (accessed October 27, 2014).

Corey, David. "Abstract." National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810624/ (accessed October 28, 2014).

Wikimedia Foundation. "Telomerase." Wikipedia. http://en.wikipedia.org/wiki/Telomerase (accessed October 28, 2014).

Wikimedia Foundation. "Telomere." Wikipedia. http://en.wikipedia.org/wiki/Telomere#Shortening (accessed October 28, 2014).

Wikimedia Foundation. "Okazaki fragments." Wikipedia. http://en.wikipedia.org/wiki/Okazaki_fragments (accessed October 28, 2014).

Scientists unravel the relation between Human height and complicated gene combinations

Currently I am studying genes and DNA (gene regulation and expression, DNA replication, damage and repair), and I searched for news on that area that might interest you. As I said in my first blog post, you will be aware of latest news and discoveries in biology.

I have found one news article on reuters.com about one study of height which makes our understanding of the relationship between height and genetics more clear. This study is considered to be largest ever since, genome information of over a quarter million persons was analyzed to identify about 700 genetic variations and more than 400 genome regions relating to human height.

In this post I am going to make you familiar with this study and explain why this study is important.

Everybody knows that the height is determined by genes and is inherited from parents. Like, if your father is tall than mostly you are probably going to be tall. However, understanding the whole concept of genetics at the background of it is a bit challenging. For hundreds of years scientists were studying human height by measuring its average, because it is a good model for studying the genetics of diseases. For example, they have estimated that the average height of men has risen by 11cm since 1870 year. 

This study found that height is closely related to inherited DNA as long as 80 percent of height variation among the population is due to DNA. The study was held by the Genetic Investigation of Anthropometric Traits (GIANT) international Consortium. They analyzed the information from the genomes of 253,287 people. Approximately 2 million common genetic variations were checked and found to appear in at least 5 % of their samples. They identified 697 single variations, located in 424 gene regions to be related to height.

You can find their report in the journal Nature Genetics .

DNA sequence variation of different levels explains the quantity of variations in that picture.

Overall, they have found that the genetic variations, the regions of DNA (genes) that vary from person to person account for 80% of influence to human height. Other 20% are given to nutrition with other environmental factors. This means that you can increase your height maximum by only 20% because 80% of height depends on genetic component (the code). People have become taller on average in the last century owing to positive factors such as improved nutrition.

The majority of the genes identified are likely to be essential regulators of skeletal growth, but their contribution was not known until now. Some genes can be liable for unexplained syndromes of abnormal skeletal growth, particularly in children.

The study helps to find out what has real impact in the treatment of disorders that may be influenced by height. These are diseases such as osteoporosis, cancer, or heart disease, which are caused by the combined effect of many genes.

Some of these have been associated with collagen, structural component of bone and with part of cartilage called chondroitin sulfate, and the growth plate area of ​​growing tissue near the ends of the long bones of the body.

Nevertheless, some of the newly discovered genes have no known function still in the regulation of height, but are promising directions for future research.

To conclude, the understanding the genetics of height, will help us to understand how the genetics of human disease work.

Reference list:

"Defining the role of common variation in the genomic and biological architecture of adult human height." nature.com. http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3097.html (accessed October 7, 2014).

"Height Is Determined By Complicated Gene Combinations." Diabetes Insider. http://diabetesinsider.com/height-determined-complicated-gene-combinations/35678 (accessed October 7, 2014).

"Scientists discover nearly 700 new genetic variations that determine height." Zee News. http://zeenews.india.com/news/health/health-news/scientists-discover-nearly-700-new-genetic-variations-that-determine-height_1480555.html (accessed October 7, 2014).

"Tall tale: scientists unravel the genetics of human height." | Reuters. http://in.reuters.com/article/2014/10/05/science-height-idINL2N0RY1YG20141005 (accessed October 7, 2014).