Genetics today

The nucleotide sequence of the human genome was published in April 2003. So far, about 25,000 genes have been identified - less than expected. It is now clear that only 2% of the genome codes for proteins. This raises a question about what the other 98% of the genome is there for.

[An excellent animation of DNA structure can be found at: www.umass.edu/microbio/chime/dna/fs_pairs.htm ]

Understanding development

Similar developmental processes occur in a wide variety of species. To learn more about human development before birth, we can study other species in which the embryos are more accessible. Current findings suggest that "the secret of embryonic development is the control of gene activity in time and space" Christiane Nüsslein-Volhard 2006.

Examples of model organisms

Valuable insights about development have been gained by the study of the following organisms:

	slime mould Dictyostelium discoideum
	nematode worm Caenorhabditis elegans
	fruitfly Drosophila melanogaster
	zebrafish Danio rerio
	chick embryo Gallus domesticus
	mouse Mus musculus

Slime mould Dictyostelium discoideum

Lifecycle of the slime mould
From Nature, 408, 917 (21/28 Dec 2000)

Free-living amoebae come together when food is scarce and form a multicellular organism. This organism - grex - migrates, and cells within it become differentiated according to their positions within the whole. Some cells form spores that will be dispersed to create a new population of amoebae, while the others will die.

Nematode C. elegans

From Nature, 354, 190 (21 Nov 1991)

All 558 cells of a newly-hatched roundworm larva and 959 somatic cells of the adult are generated by strict cell lineages. There is no regulation (adaptability) of the sort seen in embryos of mammals, for example. However, widely-conserved signalling pathways are required to properly specify the cell lineages.

Fruitfly - Drosophila

From Scientific American, Jul 1990 p27

The fruitfly has a short generation time – the larva hatches in 1 day, the adult fly emerges by 12 days. Morgan (1866-1945) catalogued fruitfly mutations affecting the wings, body colour, arrangement of bristles, and structure of the eyes. Multiple copies of chromosomes - 'giant' chromosomes - occur in some tissues such as the salivary glands, giving the chromosomes a banded pattern and making it possible to locate genes.

Zebrafish Danio rerio

From Nature, 369, 19 (5 May 1994)

Chick embryo Gallus domesticus

Mouse Mus musculus

From Deepak Srivastava, www.gladstone.ucsf.edu/gicd/srivastava

Molecular pre-patterns

The earliest steps in development after fertilisation are controlled by maternal factors. These are placed in the egg as it is being formed. For example, mRNA for the bicoid protein is anchored at the future head-end of the Drosophila egg. These maternal factors regulate the activity of zygotic genes - they are transcription factors.

Bicoid mRNA, from Nature, 445, 497 (1 Feb 2007)

Bicoid protein (red), caudal protein (green)
from Nature, 379, 676 (22 Feb 1996)

Morphogenetic gradients

Different concentrations of a maternal factor elicit different responses within nuclei. Gradients of substances within the embryo can create zones with different identity - they provide positional information. In general, the gradients of maternal factors regulate the transcription of zygotic segmentation genes - the gap genes.

Transcription factors

The protein products of regulatory genes attach to specific control regions on the DNA. These transcription factors can either activate or repress particular genes. Mutations in maternal regulatory genes result in large regional changes (eg: lack of head or tail), while mutations in zygotic genes tend to result in more localised changes.

Zygotic genes

More complex patterns occur when the zygotic genes become active and specify their own transcription factors. Gap genes activate pair-rule genes. Pair-rule genes activate segment-polarity genes, producing the 14 main segments of the larva (and later the fly). "Control of gene activity by transcription factors is a central element in shaping life in time and space." C. Nüsslein-Volhard, 2006 p35

Homeotic genes

Homeotic genes are selector genes that cause different cells to adopt different states after the main regions have been established. Homeotic genes are found in all animal species examined so far and some plants. If a homeotic gene mutates, it may cause the conversion of one body part into another.

Sequence of homeobox genes in fruit fly and mouse
From Nature, 376, 479 (10 August 1995)

Homeobox

All homeotic genes contain an identical sequence of 180 nucleotides. This sequence enables the transcription factor derived from the gene to bind with DNA and switch other genes on or off. This shared sequence is called the homeobox. Genes containing this sequence are known as homeobox genes (or Hox genes in vertebrates).

Arrangement of Hox genes

Hox genes occur in clusters in the same order on the chromosomes as the order of the parts of the body they regulate during development. Thus, Hox genes affecting regions nearer the head are at one end of the cluster and genes affecting tail regions are at other end. Hox genes affecting head regions are expressed before those affecting the tail regions.

Drosophila has 8 homeotic genes, in 2 clusters. Humans have four Hox clusters - A, B, C, and D - containing a total of 39 homeotic genes.

Mutations in homeotic genes

In Drosophila, a single homeotic gene can regulate development of a whole structure. A mutation in that gene might result in an inappropriate structure being formed. In one mutation, Antennapedia, flies develop legs in place of their antennae.

Conserved sequences

It appears that Hox genes arose early during evolution and have been conserved because of their key role in embryonic development.

Hierarchy of genes

There is "a hierarchy of gene function: those genes that are active early in the process control the effects of those genes that are active later on." Christiane Nüsslein-Volhard, 2006 p55