Although many of our studies have begun in mice or sticklebacks,
we would ultimately like to understand the molecular basis of human traits as well. What are the genetic mechanisms
that underlie the unique suite of morphological, physiological, and behavioral characters seen in humans, including
our unique skeletal structures, intelligence, lifespan and disease susceptibilities? Although these questions are
amongst the most challenging in all of science, humans have exceptionally well developed genetic and genomic
resources, including a rapidly growing collection of completely sequenced individuals, and the most detailed
population genetics of any species on earth. We have shown that genes and mechanisms that we first identified in mice
or sticklebacks also turn out to control major differences in human morphology, human disease
incidence, and classic differences in skin and hair color in millions to billions of people around the world
(Ho et al. 2000;
Pendleton et al. 2002;
Gurley et al. 2006;
Miller et al. 2007;
Guenther et al. 2014).
Building on this work, we have now begun a variety of new projects to identify genomic mechanisms that underlie
the evolution of key human traits. These studies combine human-specific sequence changes detectable by comparative
genome analysis (with Gill Bejerano's lab at Stanford), patterns of
evolutionary change we have previously learned in sticklebacks, signatures of selection in human populations, and
functional tests of human-specific sequence changes using mouse models
(Guenther et al. 2014).
Using this combination of approaches, we have recently searched the human genome for regulatory deletions that are
similar to the kind we already know control major morphological change in sticklebacks. This work has identified over
500 positions where humans are missing conserved non-coding sequences compared to our closest relatives the
chimpanzee. Experimental tests in mice link three of the human specific molecular deletions with interesting traits
that have also evolved specifically in the human lineage, including absence of sensory whiskers and penile spines
in our own species (regulatory deletion in the Androgen Receptor gene), expansion of neural structures in particular
brain regions (regulatory deletion in the tumor suppressor gene GADD45g), and changes in specific toe lengths in
hindlimbs when humans evolved upright walking (regulatory deletion in the bone morphogenetic protein gene GDF6)
(McLean, Reno, Pollen et al. Nature 2011;
Indjeian et al. Cell 2016).
Experiments with many other regions are currently underway. We are still a long way from knowing the genomic
mechanisms that have made us human. However, we believe that molecular mechanisms contributing to human-specific
traits can now be studied, and that progress in this area will lead to important new insights into both human health
and human disease.
More information on research projects in mice and sticklebacks.
More information on "Penile Spines" versus "Pearly Penile Papules" in Humans.