Characterising selection in Conserved Noncoding Elements (CNEs)
Abstract
Comparative genomic studies have identified noncoding regions of the genome which
are often more highly conserved between species than protein-coding sequences. One
possible explanation for this conservation of non-coding sequences is some form of
selective constraint since sequence conservation at great evolutionary depths is a
preliminary indication of functional constraint. Here, I consider nearly 2500 putative
regulatory elements, termed Conserved Noncoding Elements (CNEs), that are conserved
across seven vertebrate species (human, macaque, mouse, chicken, frog, zebrafish and
fugu). I distinguish between CNEs that show accelerated rates of evolution and those
that have remained more constrained throughout evolution, and identify CNEs that show
higher than expected substitution rates in the human lineage that may be potential
candidates of adaptive evolution. However, it is not trivial to demonstrate the action of
selection on such sequences. It is relatively easier in the case of protein-coding DNA,
since selection would be predicted to result in different rates of substitution for
synonymous and non-synonymous sites. Hence, I use the same seven species to define
phylogenetically invariant positions in CNEs in contrast to those that have at least one
substitution and analyse them independently to determine if there is a positive
correlation between evolutionary conservation and the strength of purifying selection at
individual sites. In the 1000 Genomes, but not the HapMap, data I find a significant
excess of rare derived alleles in CNEs relative to coding sequences. This excess of rare
alleles can be best explained if selection is relatively consistent across sites, with most
mutations resulting in a similar reduction in fitness. Finally, I explore patterns of
variation in the allele-frequencies within human populations, however do not detect any
significant differences in the underlying distribution of negatively selected variants
among human populations.
Authors
De Silva, Dilrini R.Collections
- Theses [4137]