Introduction to Genomics

Genomics

The study of genomes, particularly the set of techniques, analytical methods, and scientific questions special to the study of complete genomes.

Genetics

The study of heredity and inherited variation.

Why study complete genomes?

• Determine what is missing from the genome
• Identify genes and pathways that are difficult to study biochemically
• Completeness: find every gene that is in a pathway of interest
  • Of course, this depends upon figuring out what genes are involved in a given pathway.
• Study non-coding regions of the genome
• Introns, promoters, telomeres, etc.
  • We probably are not yet aware of all regulatory and structural features found in genomes
• Provide large databases that are amenable to statistical methods
• Identify variant sequences that may have subtle phenotypes
• Study evolution of the organism and genome

Intra-genomic studies

Analyses of gene families and superfamilies

Protein kinases

ATP-binding cassette (ABC) transporters

Multidrug-resistant transport proteins

Physical map of chromosomes

Isochores

Regions with distinctive base composition

Associated with patterns of gene expression & recombination

Error-prone sequences

EXAMPLE

Identification of uncharacterized genes

Roughly 2000 open reading frames (about half) in the yeast genome have no homolog of known biochemical function

URFs -- Unidentified open Reading Frames

Comparable numbers of URFs have been found in other genomes

Possible explanations for URFs

Rapid sequence evolution makes identity of sequence obscure

Improved sequence matching algorithms can help reduce this category

Gene encodes a genuinely novel product

Need to do follow-up biochemical work

But the availability of the sequence provides a powerful tool for identifying gene function.

Identification of non-protein information

Comparative studies

Identify core set of genes for all organisms

Identify contents of ancestral genome

Is there any real 'model organism'? If so, what is it?

Do all organisms use the same gene for the same purpose?

The answer here is clearly "no".

Example:

When the genome of the archaean Methanococcus jannaschii was sequenced, four of the 20 amino-acyl-tRNA synthetases could not be found.

These enzymes are critical in preparing the tRNAs for protein synthesis.

Biochemical evidence indicated that glutamine and asparagine are incorporated as transamindated derivatives of glutamate and aspartate, so the absence of these tRNA synthetases was not surprising.

A comparable story was postulated for cysteine, hypothesizing that cysteine-tRNA is produced by trans-sulfuration of serine-tRNA.

But the absence of lysyl tRNA synthetase was unexplained.

Subsequently the lysine-tRNA synthetase was identified -- it is dissimilar to the other tRNA syntetases, apparently a new class.

Not the product of rapid evolution.

The bacteriuim Borrelia burgdorferi was subsequently found to have the same kind of lysine-tRNA synthetase as that found in M. jannaschii

Likely explanations:

Parallel evolution

Horizontal gene transfer & substitution

What is the relative importance of horizontal gene transfer in evolution?

It is now clear that horizontal gene transfer has played a significant role in evolution

But the full measure of its importance is still a subject for active study

Other questions answerable by comparative genomics

Doolittle, R.F. 1998. Microbial genomes opened up. Nature 392:339-342.

Clayton, R.A., O. White, K.A. Ketchum, and J. C. Venter. 1997. The first genome of the third domain of life. Nature 387:459-462.

List of complete genomes and genomes in progress: http://www.tigr.org/tdb/mdb/mdb.html

Database of genome sizes: http://www.cbs.dtu.dk/databases/DOGS/index.html