Complementary evolution of coding and noncoding sequence underlies mammalian hairlessness

Body hair is a defining mammalian characteristic, but several mammals,
such as whales, naked mole-rats, and humans, have notably less hair than
others. To find the genetic basis of reduced hair quantity, we used our
evolutionary-rates-based method, RERconverge, to identify coding and
noncoding sequences that evolve at significantly different rates in
so-called hairless mammals compared to hairy mammals. Using RERconverge,
we performed an unbiased, genome-wide scan over 62 mammal species using
19,149 genes and 343,598 conserved noncoding regions to find genetic
elements that evolve at significantly different rates in hairless mammals
compared to hairy mammals. We show that these rate shifts resulted from
relaxation of evolutionary constraint on hair-related sequences in
hairless species. In addition to detecting known and potential novel
hair-related genes, we also discovered hundreds of putative hair-related
regulatory elements. Computational investigation revealed that genes and
their associated noncoding regions show different evolutionary patterns
and influence different aspects of hair growth and development. Many genes
under accelerated evolution are associated with the structure of the hair
shaft itself, while evolutionary rate shifts in noncoding regions also
included the dermal papilla and matrix regions of the hair follicle that
contribute to hair growth and cycling. Genes that were top-ranked for
coding sequence acceleration included known hair and skin genes KRT2,
KRT35, PKP1, and PTPRM that surprisingly showed no signals of evolutionary
rate shifts in nearby noncoding regions. Conversely, accelerated noncoding
regions are most strongly enriched near regulatory hair-related genes and
microRNAs, such as mir205, ELF3, and FOXC1, that themselves do not show
rate shifts in their protein-coding sequences. Such dichotomy highlights
the interplay between the evolution of protein sequence and regulatory
sequence to contribute to the emergence of a convergent phenotype.