INSIGHTS | PERSPECTIVES
1534 23 DECEMBER 2016 • VOL 354 ISSUE 6319 sciencemag.org SCIENCE
the sweat gland–producing region to cover
the body (8). This alteration allowed people
to have improved heat tolerance, which
enabled them to run long distances in big
game hunting while maintaining their body
temperature. Does similar circuitry function
in controlling hair versus sweat gland fate
determination in humans? Lu et al. found
high BMP activity spikes around 17 weeks of
gestation, shifting placode fates from hairs
to glands. Thus, similar sweat gland–
forming circuitry is activated by spatial signals
in mice but by temporal signals in humans.
The next challenge will be to find out how
BMPs are regulated spatiotemporally.
There are many more examples in which
modification of the integument helps ani-
mals adapt to their changing environment.
For example, the tooth changes shape in re-
lated rodents to enable optimal use of their
diets (9). In filter feeding, baleen whales’
tooth formation is shut off and modified
hair bundles form in the mouth cavity in-
stead (see the photo). At the macroevolu-
tionary level, changes in integument organs
help define a whole new vertebrate class
(10). For example, the conversion of scaly in-
tegument to feathers in feathered dinosaurs
was the prelude to the birth of the bird as a
whole new class (11, 12). And in mammals,
the evolution of mammary glands helps de-
fine the mammalian class (13, 14). Thus, the
ensemble of modules (hair or feather fol-
licles) allows the generation of a complex
integument that is highly adaptable. Modu-
lation of integument phenotypes can occur
at the genomic level with consequences at
the evolutionary scale, or at the epigen-
etic level with metamorphic changes in the
same individual, or in the same species but
at different ages, sexes, and seasons (15).
Understanding the “tao” of the integument can also lead to medical benefits.
With the progress of stem cell biology, scientists now have access to ectodermal progenitors. These new insights will help our
efforts to guide these progenitors into new
integument organ phenotypes for regenerative medicine. j
REFERENCES AND NOTES
1. C.-M. Chuong, Ed., Molecular Basis of Epithelial Appendage
Morphogenesis (Landes Bioscience, Austin, TX, 1998).
2. D. Dhouailly, Wilhelm Roux’s Arch. Dev. Biol. 177, 323
3. C. P. Lu, L. Polak, B. E. Keyes, E. Fuchs, Science 354,
4. C.-M.Chuong, C.Y.Yeh,J. Ting-Xin,R.B.Widelitz, Wiley
Interdisc. Rev. Dev. Biol. 2, 97 (2013).
5. C.-M. Chuong et al., Physiology 27, 61 (2012).
6. J. M. Hebert et al ., Cell 78, 1017 (1994).
7. M. Plikus et al., Am. J. Pathol.164, 1099 (2004).
8. Y. G. Kamberov et al ., Proc. Natl. Acad. Sci. U.S.A .112, 9932
9. J.Jernvall, S.V.Keränen,I. Thesleff, Proc.Natl.Acad.Sci.
U.S.A. 97, 14444 (2000).
10. P. Wu etal., Int.J.Dev.Biol.48,249(2004).
11. C.-M. Chuong et al., J. Exp. Zool. B 298, 42 (2003).
12. X. Xu et al ., Science346, 1253293 (2014).
13. O. T. Oftedal, Animal 6, 355 (2012).
14. R. B. Widelitz et al ., Semin. Cell Dev. Biol. 18, 255 (2007).
15. M. Lei, C.-M. Chuong, Science 351, 559 (2016).
Supported by NIH grants AR42177 and AR60306 (C.-M.C.),
grants from China Medical University Hospital, and a fellowship
from National Tai wan University (Y.C.L.). We thank R. Widelitz
and P. Wu for help with the manuscript.
Rare genetic variants are
linked to electronic health
record phenotypes at a
By Daniel J. Rader and Scott M. Damrauer
One of the greatest challenges of the biomedical enterprise is to link human genetic variation with pheno- typic traits at a population scale. Such efforts have myriad benefits, includ- ing the illumination of basic human
biology, the early identification of prevent-able and treatable illnesses, and the identification and validation of new therapeutic
targets, thus enabling the promise of precision medicine to improve human health.
On page 1549 of this issue (1), Dewey et al.
report findings from their effort to couple
whole-exome sequencing (WES) with longitudinal electronic health record (EHR) phenotype data in more than 50,000 individuals
(DiscovEHR). They identified hundreds of
individuals with rare “putative loss-of-function” (pLoF) gene variants linked to
novel phenotypes. On page 1550 of this issue,
Abul-Husn et al. (2) report on a companion
study that identified many participants with
familial hypercholesterolemia who had not
been diagnosed or treated. These results
demonstrate the enormous potential of this
approach for promoting scientific biomedical discovery and influencing the practice of
Previous studies have used high-throughput identification (silicon chip-based genotyping) of known common variants in EHR
cohorts (3) or applied WES [a technique
for sequencing all the expressed genes
(exome) in a genome] for rare variant
discovery to case-control cohorts for complex diseases (4). However, the approach by
Dewey et al. and Abul-Husn et al. is notable
because of the application of large-scale WES
to a phenotypically rich EHR cohort. Popu-
Departments of Genetics, Medicine, and Surgery, Perelman
School of Medicine, University of Pennsylvania, and Corporal
Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia,
PA 19104, USA. Email: firstname.lastname@example.org
In very early vertebrates, the
integumentary surface was smooth,
containing an epidermal and
Periodic patterning evolved to
partition integuments into multiple
elements, each with stem cells that
allow cyclic renewal. Regional
specifcity also evolved (blue and red).
Morphogen signaling at diferent
developmental time points and
locations evolved to modulate the
form of integumentary elements,
enabling them to adapt to changing
Hair and other
Organizing to adapt
Periodic patterning enables the formation of complex yet adaptable integument organs.