Discuss the Impact of Genome Sequences on the Study of Development
Cells and Development
Discuss the Impact of Genome Sequences on the Study of Development
Development refers to the biological process an organism undergoes during growth. The introduction of genetics this century has greatly accelerated our understanding in this field. It appears to be exponential, continually more scientists are being drawn into the field and more data is being generated. In this essay I will briefly outline the course of development as a subject over the past 100 years (with a slight bias towards animal development) commenting on how important the use of model organisms has become and the contribution to the field their genomes have made.
Development started with Aristotle in the 4th century BC. He noted the different ways in which animals were born, oviparity, viviparity etc, and began to look at the transition from conception to adulthood. Not much happened in the study for about 2000 years, until a man named William Harves in 1651 made the profound statement that all animals are from eggs, "ex ovo omnia". The subject never really took off because the specimens were too small to analyse. The invention of the microscope revolutionised the science and allowed study of these once unseen structures. This coupled with the Morgan's' use of Mendel's' genetic theory to create the chromosomal theory of inheritance allowed scientists to begin to make quantitative assessments and start asking new questions.
Despite it's hazy and undramatic origins the field aquired a recognisble unity by the 1930's. One proposed question was "how do the organisms' genes produce their effect in development?" This lead to the field of developmental genetics, using the genes of an organism to explain it's development. During that period Lillie (1927) Spemann (1938) and Just (1939) said there would be no genetic theory of development until:
. Genetisists could explain how chromosomes produce different and changing types of cell cytoplasms.
2. Genetisists could explain how genes control the earley stages of development.
3. And explain how complex phenomena, such as the sex determination mechanisms occur.
The use of mutants at that time was very important in order to understand the wild type phenotypes. But still there was a huge conceptual gap between genes and phenotype. Work done in the 1940's showed the site specificity of genes, being expressed in some but not all tissues. Also a temporal attribute was added to genes, i.e. they were only active for a certain period of time. Thus identifying an ordered sequence of differential gene expression. This suggested a relationship between genes and the changes that occur during development. Watson and Crick provided the model for DNA, and genes were now understood to be sequences of chemical information as opposed to the previous theories that they somehow interacted with enzymes.
However this discovery did not infuse itself into the world of developmental genetics until mRNA was discovered. This carrier molecule linked genes from the nucleus with the site of protein synthesis. The response from the biological community was huge, as it finally linked gene activities and their regulation. Thus began the age of molecular biology, and it has had many profound effects on the study of development.
During this time, a series of experimental techniques had been developed that were able to augment developmental studies. The major interest of that time was clonal analysis. Clonal analysis ...
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However this discovery did not infuse itself into the world of developmental genetics until mRNA was discovered. This carrier molecule linked genes from the nucleus with the site of protein synthesis. The response from the biological community was huge, as it finally linked gene activities and their regulation. Thus began the age of molecular biology, and it has had many profound effects on the study of development.
During this time, a series of experimental techniques had been developed that were able to augment developmental studies. The major interest of that time was clonal analysis. Clonal analysis onvolves the tracking, during development, the mitotic divisions of a cell - its cell lineage - made distinguishable from the surrounding cells by the presence of a distinctive genetic "marker" in those cells. This allowed developmentalists to ask questions about the behaviour of normal cells during development and the localised effects of mutations. Clonal analysis in it's various forms emphasised the cell as the unit of development and truly bridged the gap between developmental biology and molecular biology. And so more has changed in development in the past 20 years than in the previous 80 in terms of the number of people working on it and the amount of data generated.
One such effect was the introduction of genomic analysis to developmental biology. The term "genome" was coined by H. Winkler (1920) by combining the terms genes and chromasomes in order to describe the complete set of chromosaomes and their genes. Whilst developmental analysis concentrated on the development of different types of organisms across different types of phyla, molecular biology adopted the use of a few select organisms, model organisms, in order to carry out their analysis. Model organisms allowed scientists all over the world to concentrate on one specific organism at a time and it was believed that more could be gained from knowing about the processes in one organism completely than only partial information about a range of organisms. The model organisms were choosen for a variety of reasons. It was important that these organisms be easily cultivated in the lab, have relatively small and uncomplicated genomes, a short generation time, be easily mutated, and be fairly degenerate with respect that they represented many aspects of their phyla, for comparative analysis within and outside of the group.
Model organisms that are in use today represent specific sections of the phylogenetic tree:
E-coli Prokaryotes
Sacchromyces cerevisiae (Yeast) Basic Eukaryotes
Aribidopsis thaliana Angiosperm plant
Caenorhabditis elegans Nematode worm
Drosophila melanogatser Insects and invertebrates
Brachydanio rerio (Zebra danios) Vertebrates
Mus musculus Vertebrates
Homo sapiens Vertebrates (not strictly a model organism but a lot of research has gone
into it)
Arabidopsis is the perfect model organism as it has many of the attributes listed above. Arabidopsis thaliana is a member of the mustard family, a typical angiosperm. It has a small genome, 120mb spread over 5 chromosomes with an estimated 20,000 genes, and having a small amount of interspersed DNA means that sequencing is very cost effective. It is also small in size, so it can be grown in a petri dish and is susceptible to mutations and agrobacterium, making it perfect for genetic experimentation.
DNA sequencing of these organisms is already well underway, and in most cases the structural annotation is nearly complete. The relevance genome sequencing has to the field of development may not be apparent at first. Developmentalists have also been working on the model organisms for many years now and are now able to relate the genes involved in the developmental pathways to the genes sequenced on the genome. Since 1996 genetic database searching became a fruitful way to do genetic research (Bassett et al 1997), called research in silico. The use of model organisms provides an important stepping stone for the analysis of other organisms, refered to a comparative genomics. In the past 20 years genome sequencing has given strong evidence that if two genes are related on the mouse genome then there is a strong chance that they will be closely linked on the human genome. This allows hypothesis to be formed about the possible functions of the genes in the unstudied organism, functional genomics.
Whilst it is important to know the temporal and spatial pattern of gene expression during development, relatively easy assays given todays technlogy, what is vital is to know the functions of the gene during development. Comparative genomics points scientists in the right direction and functional genomics provides hypothesis to work with.
The use of comparative genomics is valuable where the organism under question is difficult to study during development, i.e. not a model organism (and even then it is not an easy task). Take Homo sapiens as an example, the genome is very big, due to gene duplications, and the genes present often have overlapping functions. That in conjunction with a long generation time and restrictions on experimentation makes the identification of the role of even a single gene in development very difficult. Thus the use of comparative genomics and functional genomics allows the scientist to create hypothesis based on the data for genes that are homologous in the model organism that have already been annotated. In view of the NAS committee (Alberts et al 1998), pursuit of genomics of other organisms is more amenable to the experimantal manipulation than the human would be for the Human Genome Project. An experimental example is in the bacterium Mycoplasma genitalium. This organism lives as a parasite in the epithelial layer of the urogenital tracts of primates. This makes it very difficult to culture, yet it's DNA sequence has been obtained and functional annotation has been completed through comparative genomics with E. coli and S. cerevisiae.
A paper that I feel really highlights how useful the advent of genomic information has been to the study of development is by Rubin et al (2000). In it he investigates the comparative genomics of eukaryotes, particularly the model organisms. The developmental strategies employed by different organisms vary greatly, from the fixed cell lineage of C elegans to the syncitial embryogenic development of the fly. However the genes used in many of the developmental processes show close homology to one another. An example would be the HOM genes of drosophila and the HOX genes of mice. Although one is a vertebrate and the other an invertebrate the genetic relationships between the two are too strong to be coincidental.
Despite the conservation of the mechanisms regulating cell cycle progression many of the functions of this progression are from protein families that are not conserved across the phyla. The cyclins of S cerevisiae share no orthologues in vertebrates yet genomic analysis of the cyclins in humans draws many strong paralells within the drosophila genome. The human cyclins A, B, B3, E and D have all been found in the fly and many have close similarities. There are many other examples of these orthologues existing in nearly all developmental processes, from the construction of the cytoskeleton to apoptosis and immunity to microbial molecules. This kind of information is very important to developmentalists as it gives clues to the divergence and conservation of certain developmental mechanisms across phyla which they can then apply in conjuction with a phylogenetic tree to make predictions about organisms which they know little developmental biology about.
Other advantages of genome sequences to developmetnal biology is that it facilitates not just the study of single genes but of networks of genes and families, for example the HOX cluster in vertebrates. This will lead to a better understanding of emergence (where the whole is greater than the parts) and give a more complete picture of the biology of an organism. Genome sequences also greatly aid the efficeincy of postional cloning in the search for the genes that play key roles in development and in some cases the effort has lead to reveal previously unkown counterparts of developmental pathways.
The future of the genome sequencing programs has been outlined by the Gene Ontology group. Established in 1998 by members of fly, mouse and yeast database programs their memebership has grown in 200 to include work from arabidopsis and worm. They are working to develop a standarised for of molecular annotation that will contribute to the unification of genome sequences from different organisms. The need for standardisation is clear given the huge amount of data availible, otherwise searching across databases would become an impossible task. This is vital to the advancement of developmental sciences and biology in general as it will provide a firmer base for comparative studies. It will display similarities between genes that scientists can then draw their own inferences.
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