One approach to the analysis of genomes is to infer important gene functions through applying

an understanding of evolution to search for expected evolutionary patterns. Another approach is

to discover evolutionary trends by studying genomes themselves. Taken together, evolutionary
insight and large genomic datasets offer great potential for discovery of novel biological
phenomena. A recurring theme of this work is to take a global computational approach to
analyzing elements of genes and RNAs encoded in the genome and use it to find interesting
new biological phenomena. We can do this by seeing how individual examples “diverge” or
differ from the average case. For example, by examining many protein–coding genes, we can
identify features representative of that class of loci. We can then come up with highly accurate
tests for distinguishing protein–coding from non–protein–coding genes. Often, these
computational tests, based on thousands of examples, will be far more definitive than
conventional low– throughput wet lab tests. (Such tests can include mass spectrometry to
detect protein products, in cases where we want to know if a particular locus is protein coding.)

As the name suggests, comparative genomics does not focus on one specific set of genomes.
The problem with purely focusing on the single genome level is that key evolutionary signatures
are missed. Comparative genomics solves this problem by comparing genomes from many
species that evolved from a common ancestor. As evolution changes a species’s genome, it
leaves behind traces of its presence. We will see later in this chapter that evolution
discriminates between portions of a genome on the basis of biological function. By exploiting
this correlation between evolutionary fingerprints and the biological role of a genomic
subsequence, comparative genomics is able to direct wet lab research to interesting portions of
the genome and discover new biological phenomena. We can glean much information about
evolution through studying genomics, and, similarly, we can learn about the genome through
studying evolution. For example, from the principle of “survival of the fittest,” we can compare
related species to discover which portions of the genome are functional elements. The
evolutionary process introduces mutations into any genome. In non-functional regions of DNA,
accumulated mutations are kept because they do not disturb the function of the DNA. However,
in functional regions, accumulated mutations often lead to decreased fitness. Thus, these
fitness-decreasing mutations are not likely to perpetuate to future generations. As time
progresses, evolutionarily unfit organisms are likely to not survive and their genes thin out. By
comparing surviving species’ genomes with their ancestors’ genomes, we can see which
portions constitute functional elements and which constitute “junk DNA.” To date various
important biological markers and phenomena have been discovered through comparative
genomics methods. For example, CRISPRs (Clustered Regularly Interspaced Short Palindromic
Repeats), found in bacteria and archaea, were first discovered through comparative genomics.
Follow–up experiments revealed that they provide adaptive immunity to plasmids and phages.
Another example, which we will look at later in this chapter, is the phenomenon of stop–codon
read–through, where stop codons are occasionally ignored during the process of translation
phase of protein biosynthesis. Without comparative genomics to guide them, experimentalists
might have ignored both of these features for many years. Without a system for interpreting and
identifying important features in genomes, all of the DNA sequences on earth are just a
meaningless sea of data. However, we cannot ignore the importance of both computer science
and biology in comparative genomics. Without knowledge of biology, one might miss the
signatures of synonymous substitutions or frame shift mutations. On the other hand, ignoring
computational approaches would lead to an inability to parse ever larger datasets emerging
from sequencing centers. Comparative genomics require rare multidisciplinary skills and insight.
This is a particularly exciting time to enter the field of comparative genomics, because the field
is mature enough that there are tools and data available to make discoveries. But it is young
enough that important findings will likely continue to be made for many years.