Comparative genomics as a tool to understand evolution and disease

Abstract

When the human genome project started, the major challenge was how to sequence a 3 billion letter code in an organized and cost-effective manner. When completed, the project had laid the foundation for a huge variety of biomedical fields through the production of a complete human genome sequence, but also had driven the development of laboratory and analytical methods that could produce large amounts of sequencing data cheaply. These technological developments made possible the sequencing of many more vertebrate genomes, which have been necessary for the interpretation of the human genome. They have also enabled large-scale studies of vertebrate genome evolution, as well as comparative and human medicine. In this review, we give examples of evolutionary analysis using a wide variety of time frames-from the comparison of populations within a species to the comparison of species separated by at least 300 million years. Furthermore, we anticipate discoveries related to evolutionary mechanisms, adaptation, and disease to quickly accelerate in the coming years.

Figure 1.

A comparative genomics display derived from the UCSC Genome Browser (Meyer et al. 2013). The top panel depicts the genomic region surrounding the 5′ end of the gene LBH (limb bud and heart development homolog) in the human genome. The top track indicates mammalian conservation as determined by phastCons (Pollard et al. 2010). Putative promoter and enhancer elements are indicated. The second track shows the intron/exon structure of the 5′ end of LBH. The 5′ untranslated region (UTR) and start site are indicated. The bottom panel shows a close up on the protein-coding portion of the first exon of LBH. Here, the top track shows the human DNA sequence, and the second track shows the degree of mammalian conservation as determined by PhyloP (Pollard et al. 2010). The bottom series of tracks shows the homologous protein sequence in selected vertebrate genomes. (N) Gaps in sequence; (=) unalignable sequence.

Figure 2.

A tree schematic depicting the relationships between the vertebrate species discussed. Important events such as the origin of therian sex chromosomes, pig domestication, human language evolution, and transposable element exaptation are indicated. Note the very different time spans used depending on the evolutionary question at hand.

Figure 3.

Hypothetical data showing how conservation can be used to identify the most likely functional variants in a disease locus. GWAS or sequencing data can be combined with constraint information and other genome annotations in the appropriate cell types to assess SNPs and other variants present on human disease-associated haplotypes. From the multitude of associated variants, one or a few candidate mutations often stand out based on the overlap of a candidate SNP (best variant indicated by star in lower panel) with constraint and other genome annotation. In a best-case scenario, careful analysis of sequence motifs overlapping the candidate variant will also identify a transcription factor binding site, splice site, or RNA structure that is altered by the candidate variant.