title: A genetic basis of variation in eccrine sweat gland and hair follicle density.
abstract: Among the unique features of humans, one of the most salient is the ability to effectively cool the body during extreme prolonged activity through the evapotranspiration of water on the skin's surface. The evolution of this novel physiological ability required a dramatic increase in the density and distribution of eccrine sweat glands relative to other mammals and a concomitant reduction of body hair cover. Elucidation of the genetic underpinnings for these adaptive changes is confounded by a lack of knowledge about how eccrine gland fate and density are specified during development. Moreover, although reciprocal changes in hair cover and eccrine gland density are required for efficient thermoregulation, it is unclear if these changes are linked by a common genetic regulation. To identify pathways controlling the relative patterning of eccrine glands and hair follicles, we exploited natural variation in the density of these organs between different strains of mice. Quantitative trait locus mapping identified a large region on mouse Chromosome 1 that controls both hair and eccrine gland densities. Differential and allelic expression analysis of the genes within this interval coupled with subsequent functional studies demonstrated that the level of En1 activity directs the relative numbers of eccrine glands and hair follicles. These findings implicate En1 as a newly identified and reciprocal determinant of hair follicle and eccrine gland density and identify a pathway that could have contributed to the evolution of the unique features of human skin.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; Department of Dermatology, Harvard Medical School and Cutaneous Biology Research Center, Mass General Hospital, Charlestown, MA 02129; The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138; Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Yana G
authors.initials: YG
authors.lastname: Kamberov
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Elinor K
authors.identifier: http://orcid.org/0000-0002-4343-3776
authors.initials: EK
authors.lastname: Karlsson
authors.affiliation: Department of Computer Science, Hofstra University, Hempstead, NY 11549.
authors.forename: Gerda L
authors.initials: GL
authors.lastname: Kamberova
authors.affiliation: Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Lieberman
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.affiliation: Department of Dermatology, Harvard Medical School and Cutaneous Biology Research Center, Mass General Hospital, Charlestown, MA 02129; tabin@genetics.med.harvard.edu bruce.morgan@cbrc2.mgh.harvard.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Morgan
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; tabin@genetics.med.harvard.edu bruce.morgan@cbrc2.mgh.harvard.edu.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Tabin
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D004439:Eccrine Glands / Q000378:metabolism*; D004475:Ectoderm / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D016678:Genome; D018859:Hair Follicle / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D020412:Multifactorial Inheritance / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable; D013045:Species Specificity
keywords: eccrine sweat gland; ectodermal appendage; ectodermal placode; engrailed 1; hair follicle