Massive turnover of functional sequence in human and other mammalian genomes

Abstract

Despite the availability of dozens of animal genome sequences, two key questions remain unanswered: First, what fraction of any species' genome confers biological function, and second, are apparent differences in organismal complexity reflected in an objective measure of genomic complexity? Here, we address both questions by applying, across the mammalian phylogeny, an evolutionary model that estimates the amount of functional DNA that is shared between two species' genomes. Our main findings are, first, that as the divergence between mammalian species increases, the predicted amount of pairwise shared functional sequence drops off dramatically. We show by simulations that this is not an artifact of the method, but rather indicates that functional (and mostly noncoding) sequence is turning over at a very high rate. We estimate that between 200 and 300 Mb (;6.5%-10%) of the human genome is under functional constraint, which includes five to eight times as many constrained noncoding bases than bases that code for protein. In contrast, in D. melanogaster we estimate only 56-66 Mb to be constrained, implying a ratio of noncoding to coding constrained bases of about 2. This suggests that, rather than genome size or protein-coding gene complement, it is the number of functional bases that might best mirror our naïve preconceptions of organismal complexity.

Integration of New Genes into Cellular Networks, and Their Structural Maturation

“…Alternatively, the reduction of strand content and aggregation propensity may reflect that, despite being already partly integrated into regulatory networks, a considerable fraction of proto-genes does not make it to higher conservation levels and are lost relatively quickly after their appearance. This is also supported by phylostratigraphic studies, which show that the highest number of founder genes typically form a peak in the youngest evolutionary strata (Tautz and Domazet-Lošo 2011), implying that proto-genes are subject to some form of turnover, similarly to what has been recently shown for functional noncoding sequence in mammals (Meader et al 2010). Gene deletion and inactivation studies show that 80-90% of genes in eukaryotes and prokaryotes can be lost individually without a significant fitness effect (Korona 2011), at least under laboratory conditions, and it has been suggested that genes that are lost easily during evolution are less important, i.e., have lower expression levels, fewer protein-protein interactions (Krylov et al 2003), or higher Figure 7 Structural robustness of proteins.…”

Seeing the forest through the gene‐trees

“…Among populations and over time, the same trait can come to be produced by different genotypes, with different relative contributions from different variants at the same genes or even from entirely different genes. 89 Phenogenetic drift is the evolutionary equivalent to the multiple genoptypes that generate the same phenotype in complex traits, and that means many paths to the same fitness. To a considerable extent, natural selection may rule the phenotypes, but drift rules the underlying genotypes.…”

Personal and population genomics of human regulatory variation

“…Protein-coding DNA constitutes ;1.5% of the human genome, but ;2.5%-15% is estimated to be functionally constrained (Mouse Genome Sequencing Consortium 2002; Lunter et al 2006;Asthana et al 2007;Meader et al 2010;Ponting and Hardison 2011). Thus, a significant amount of functionally important DNA is located in noncoding regions, and genetic variation in such regions likely makes a significant contribution to phenotypic variation and disease susceptibility among individuals.…”