Evidence of uneven selective pressure on different subsets of the conserved human genome; implications for the significance of intronic and intergenic DNA

Abstract

Background: Human genetic variation produces the wide range of phenotypic differences that make us individual. However, little is known about the distribution of variation in the most conserved functional regions of the human genome. We examined whether different subsets of the conserved human genome have been subjected to similar levels of selective constraint within the human population. We used set theory and high performance computing to carry out an analysis of the density of Single Nucleotide Polymorphisms (SNPs) within the evolutionary conserved human genome, at three different selective stringencies, intersected with exonic, intronic and intergenic coordinates.

Results: We demonstrate that SNP density across the genome is significantly reduced in conserved human sequences. Unexpectedly, we further demonstrate that, despite being conserved to the same degree, SNP density differs significantly between conserved subsets. Thus, both the conserved exonic and intronic genomes contain a significantly reduced density of SNPs compared to the conserved intergenic component. Furthermore the intronic and exonic subsets contain almost identical densities of SNPs indicating that they have been constrained to the same degree.

Conclusion: Our findings suggest the presence of a selective linkage between the exonic and intronic subsets and ascribes increased significance to the role of introns in human health. In addition, the identification of increased plasticity within the conserved intergenic subset suggests an important role for this subset in the adaptation and diversification of the human population.

Figure 1

Bar Chart displaying SNP density for 2003 study [14], compared to the present study (2009).

Figure 2

Bar charts demonstrating SNP densities with the conserved (A) and non-conserved (B) regions of the human genome as determined by pairwise alignment with nine other species (Pt; Pan troglodytes, Rm; Rhesus Macaque, Cn; Canis familiaris, Mm; Mus musculus, Rn; Rattus novergicus, Md; Monodelphis domestica, Gg; Gallus gallus, Xt Xenopus tropicalis, Dr; Danio rerio) at three different selective stringencies (70%; black bars, 80% grey bars; 90%; white bars over 100 base pairs) showing the number of SNPs per kilobase (y-axis) plotted against species (x-axis) that increases in evolutionary "depth" from left to right.

Figure 3

Bar chart demonstrating mean SNP densities within different subsets of the conserved genome as determined using pairwise analysis at 70% conservation with nine different species. X-axis shows increasing evolutionary depth.