Title:
Function elements in the mammalian genomes
Abstract:
Ultraconserved elements are stretches of consecutive nucleotides that are perfectly conserved in multiple mammalian genomes. Although these
sequences are identical in the reference human, mouse, and rat genomes, we identified numerous polymorphisms within these regions in the human
population. To determine whether polymorphisms in ultraconserved elements may affect fitness, we genotyped unrelated human DNA samples at loci
within these sequences. For all single nucleotide polymorphisms tested in ultraconserved regions, individuals homozygous for derived alleles
(alleles that differ from the rodent reference genomes) were present, viable, and healthy. The distribution of allele frequencies in these samples
argues against strong, ongoing selection as the force maintaining the conservation of these sequences. We then used two methods to determine the
minimum level of selection required to generate these sequences. Despite the lack of fixed differences in these sequences between humans and
rodents, the average level of selection on ultraconserved elements is less than that on essential genes. In addition, a small number of
ultraconserved elements appear to evolve faster than expected under a neutral model. The strength of selection associated with ultraconserved
elements suggests that deleting these regions may have only subtle phenotypic consequences not easily detected in the laboratory.