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Unusual chromosomes and their properties
Types of artificial chromosomes

HAC – Human artificial chromosome

Human artificial chromosome was constructed from scratch during the 1990s in human fibrosarcoma cell line (fibrous connective tissue containing tumor). This was accomplished by adding alpha-satellite DNA to telomeric and genomic DNA, which resulted in a completely new 47th microchromosome. Its length can go up to 10,000 kb (including the inserted DNA of interest) making it smaller than half of regular human chromosomes (out of haploid chromosome number – 23).

The good thing about human artificial chromosome is that it is completely independent. Unlike yeast and bacterial artificial chromosomes which are based on plasmids and integrate themselves into the genome, human artificial chromosome is constructed de novo, with all the regular parts of a chromosome (centromeres, telomeres, etc.). This means that it won’t disrupt the existing genetic material when inserted in the cell, which is important since YACs are the least stable, while BACs are also less stable than HACs, as their integration can lead to unpredictable expression levels or some other problems when the host cell’s genome is interrupted with their DNA.

Scientists are creating HACs in two ways. One of them is de novo, but it poses some problems because making a chromosome from scratch has some limitations – some specific elements like centromeres might not be constructed correctly, or some DNA fragments might not successfully integrate into them.

Another way of creating HACs is by using one already present normal human chromosome. Namely, existing chromosome is modified by cutting off some of its parts, and then some additional DNA is added at some specific sites (also known as Cre-Lox recombination).

Human artificial chromosomes can be used for a number of different things; for example, as gene transfer vectors in expression studies, for determining the function of human chromosomes, for annotating of the human genome, or for doing some specific things in the cell by carrying additional specific genes that would help in fighting some diseases, for example.
How about the entire genome?

Instead of creating only one artificial chromosome, scientists have actually managed to synthesize the entire genome of bacteria. A team of scientists from the J. Craig Venter Institute (JCVI) led by Craig Venter has accomplished this by combing two already existing techniques to transfer new DNA material into bacterial cells. The first one is actually the synthesis of a new genome, and the second one is its transfer into the cell (using nuclear transfer techniques from in vitro fertilization). In the end, scientists have produced the bacteria with synthetic genome capable of self-replication, which is awesome.

The bacterium used is Mycoplasma mycoides. Venter’s team has used its genome as a base to create the new one. It does not sound that it is synthetic at first, but they have actually added a lot of different DNA sequences into the genome, while some others were deleted, and the transplant worked in the end. Moreover, the whole process was done synthetically because, in the words of Craig Venter: “…the cell is totally derived from a synthetic chromosome, made with four bottles of chemicals on a chemical synthesizer, starting with information in a computer…”. The recipient bacterium used was Mycoplasma capricolum, and the resulting genome was around 1000 kb long.

The idea of building artificial genome has actually started some 15 years before, when the scientists have started developing the strategy to build the synthetic genome of M. genitalium, a bacterium with the smallest complement of genes capable of independent growth. Not only that it contains less than 500 protein-coding genes, but more than 100 of them can actually be removed if disrupted one at a time. They have accomplished this by assembling small 6 kb pieces of DNA into a larger molecule. The process was done both in vitro using enzymes and in vivo in yeast (for recombination).

All of this research is leading to the new era of synthetic biology, that will give rise to new ways of, for example, faster vaccine production, usage of light energy, water cleaning, etc.
The New Yeast Artificial Chromosome - SynIII

Scientists have managed to synthesize completely new chromosome from one of yeast’s 16 chromosomes. Namely, the team from the Langone Medical Centre at New York, led by Jef Boeke, has used yeast’s chromosome III and made the new one synIII (synthetic III).

The new chromosome had a lot of stuff removed. These were the things scientists thought are not necessary for the proper functioning of yeast. They are mostly some non-coding DNA (also called junk DNA or introns), some jumping genes (transposons) and some repetitive sequences (like subtelomeric repeats).

Boeke and his team have also managed to insert some new sequences as well. They were able to introduce a new function into the chromosome named “chemical switch”. It basically simplifies further genetic modifications by allowing scientists to get different variations of the same chromosome through the genome scrambling. This is important since it allows them “to generate millions of variant daughter genomes, and screen them for interesting properties,” as the leader of the project Jef Boeke said.

They have achieved this by first synthesizing shorter sequences of the DNA and then merging them together. The end result was astonishing. The original chromosome had more than 315 kb, while the new one has around 270 kb, which is around 45 kb less, or around 15% less of genetic material. Even so, the new yeast cells were able to perform all the regular activities like grow and divide, ferment sugar, etc.

This whole project is very important since it moves us one step closer to modifying our human genomes. Yeast cells are eukaryotic, and they are much more similar to ours than bacterial cells are, even though our genome is a lot larger and more complicated. Once we improve our technology in this field even more, we could do all sorts of things. For example, we could improve our immune system, fight cancer easier, slow down the effects of aging, etc. But we could also do something more fancy, like boost our memory or add the ability to see ultraviolet light. The possibilities are endless…

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Unusual chromosomes and their properties00