NeEUR/NeASN is 1.29 [95% confidence interval
(CI) of 1.15 to 1.57] and that East Asians received 20.2% (95% CI of 13.4 to 27.1%) more
Neandertal sequence in the second pulse (10).
We note that additional unexplored models may
provide a better fit to the data, and refining demographic models of hominin evolution is an
important area for future work.
The collection of surviving Neandertal lineages
that we identified allows us to search for signatures of adaptive introgression (15, 16). First,
we used introgressed variants that exhibit large
allele frequency differences between Europeans
and East Asians (FST > 0.40, P < 0.001 by simulation) (10) to identify four significantly differentiated regions (Fig. 4 and table S10) (10).
Introgressed haplotypes in two of these regions
span genes that play important roles in the integumentary system: BNC2 on chromosome 9
and POU2F3 on chromosome 11. BNC2 encodes
a zinc finger protein expressed in keratinocytes
and other tissues (17) and has been associated
with skin pigmentation levels in Europeans (18).
The adaptive haplotype has a frequency of ~70%
in Europeans and is completely absent in East
Asians (Fig. 2B). POU2F3 is a homeobox transcription factor expressed in the epidermis and
mediates keratinocyte proliferation and differentiation (19, 20). The adaptive haplotype in East
Asians has a frequency of ~66% and is found at
less than 1% frequency in Europeans (Fig. 2B).
No coding introgressed variants were found in
BNC2 or POU2F3, although several highly differentiated introgressed variants were located in
functional noncoding elements (21) (Fig. 2B),
suggesting that modern humans acquired adaptive regulatory sequences at these loci. We also
searched for shared signatures of adaptive introgression between East Asians and Europeans,
identifying six distinct regions that have introgressed haplotype frequencies greater than 40%
in both populations (Fig. 4 and table S11) (P <
10−4 by simulation) (10). One of these regions
lies in the type II cluster of keratin genes on 12q13
(table S11), further suggesting that Neandertals
provided modern humans with adaptive variation for skin phenotypes. In total, 8 of the 10 candidate introgressed regions overlap protein-coding
genes (Fig. 4).
This study shows that the fragmented remnants of the Neandertal genome carried in the
DNA of modern humans can be robustly identified, allowing, in aggregate, substantial amounts
of Neandertal sequence to be recovered. In principle, our approach can be used in the absence
of an archaic reference sequence, potentially allowing the discovery and characterization of previously unknown hominins that interbred with
modern humans (22–24). This fossil-free paradigm of sequencing archaic genomes holds
considerable promise for revealing insights into
hominin evolution, the population genetics characteristics of archaic hominins, how introgression has influenced extant patterns of human
genomic diversity, and narrowing the search for
genetic changes that endow distinctly human
References and Notes
1. A. D. Twyford, R. A. Ennos, Heredity 108, 179–189 (2012).
2. D. Zinner, M. L. Arnold, C. Roos, Evol. Anthropol. 20,
3. R. E. Green et al., Science 328, 710–722 (2010).
4. D. Reich et al., Nature 468, 1053–1060 (2010).
5. M. Meyer et al., Science 338, 222–226 (2012).
6. A. Eriksson, A. Manica, Proc. Natl. Acad. Sci. U.S.A. 109,
7. M. A. Yang, A. S. Malaspinas, E. Y. Durand, M. Slatkin,
Mol. Biol. Evol. 29, 2987–2995 (2012).
8. S. Sankararaman, N. Patterson, H. Li, S. Pääbo, D. Reich,
PLOS Genet. 8, e1002947 (2012).
9. J. D. Wall et al., Genetics 194, 199–209 (2013).
10. Supplementary materials are available on Science
11. V. Plagnol, J. D. Wall, PLOS Genet. 2, e105 (2006).
12. G. R. Abecasis et al., Nature 491, 56–65 (2012).
13. W. Enard et al., Nature 418, 869–872 (2002).
14. M. Currat, L. Excoffier, Proc. Natl. Acad. Sci. U.S.A. 108,
15. F. L. Mendez, J. C. Watkins, M. F. Hammer, Am. J.
Hum. Genet. 91, 265–274 (2012).
16. L. Abi-Rached et al., Science 334, 89–94 (2011).
17. A. Vanhoutteghem, P. Djian, Proc. Natl. Acad. Sci. U.S.A.
103, 12423–12428 (2006).
18. L. C. Jacobs et al., Hum. Genet. 132, 147–158 (2013).
19. A. Cabral, D. F. Fischer, W. P. Vermeij, C. Backendorf,
J. Biol. Chem. 278, 17792–17799 (2003).
20. H. Takemoto et al., J. Dermatol. Sci. 60, 203–205 (2010).
21. B. E. Bernstein et al., Nature 489, 57–74 (2012).
22. J. D. Wall, K. E. Lohmueller, V. Plagnol, Mol. Biol. Evol.
26, 1823–1827 (2009).
23. M. F. Hammer, A. E. Woerner, F. L. Mendez, J. C. Watkins,
J. D. Wall, Proc. Natl. Acad. Sci. U.S.A. 108, 15123–15128
24. J. Lachance et al., Cell 150, 457–469 (2012).
Acknowledgments: We thank members of the Akey
laboratory, S. Browning, B. Browning, and J. Duffy for critical
feedback related to this work; S. Pääbo for providing access
to high-coverage Neandertal sequence data; and L. Jáuregui
for help in figure preparation. A description of where
sequence data used in our analyses can be found in the
supplementary materials. Introgressed regions and variants
can be downloaded from http://akeylab.gs.washington.edu/
downloads.shtml. J.M.A. is a paid consultant of Glenview
Materials and Methods
Figs. S1 to S15
Tables S1 to S11
12 September 2013; accepted 6 December 2013
Published online 29 January 2014;
Molecular Editing of Cellular
Responses by the High-Affinity
Receptor for IgE
Ryo Suzuki,1 Sarah Leach,1 Wenhua Liu,2 Evelyn Ralston,2 Jörg Scheffel,1 Weiguo Zhang,3
Clifford A. Lowell,4 Juan Rivera1*
Cellular responses elicited by cell surface receptors differ according to stimulus strength. We investigated
how the high-affinity receptor for immunoglobulin E (IgE) modulates the response of mast cells to a
high- or low-affinity stimulus. Both high- and low-affinity stimuli elicited similar receptor phosphorylation;
however, differences were observed in receptor cluster size, mobility, distribution, and the cells’ effector
responses. Low-affinity stimulation increased receptor association with the Src family kinase Fgr and shifted
signals from the adapter LAT1 to the related adapter LAT2. LAT1-dependent calcium signals required for
mast cell degranulation were dampened, but the role of LAT2 in chemokine production was enhanced,
altering immune cell recruitment at the site of inflammation. These findings uncover how receptor
discrimination of stimulus strength can be interpreted as distinct in vivo outcomes.
It has long been recognized that there are many subtleties in how receptors function to determine a cell’s response. For example, vegetative growth of the yeast Saccharomyces cerevisiae is elicited by low pheromone concen- trations recognized by the pheromone receptor
Ste2, whereas intermediate and high pheromone
concentrations sensed by this receptor lead to
chemotropic growth or mating, respectively (1).
Mathematical modeling suggests that yeast translate pheromone concentration as the duration of
the transmitted signal (2).
We explored how the high-affinity immunoglobulin E (IgE) receptor FceRI discriminates
high- from low-affinity stimulation to modulate
the mast cells’ effector responses. Engagement
of FceRI on mast cells and basophils is central
to allergic responses (3, 4). Allergic individuals
may produce IgE antibodies to offending allergens (a term used for allergy-inducing antigens).
These IgE antibodies bind [via their crystallizable
1Laboratory of Molecular Immunogenetics, National Institute
of Arthritis and Musculoskeletal and Skin Diseases, Bethesda,
MD 20892, USA. 2Light Imaging Section, Office of Science
and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA. 3Depart-
ment of Immunology, Duke University School of Medicine,
Durham, NC 27710, USA. 4Department of Laboratory Medicine,
University of California, San Francisco, CA 94143, USA.
*Corresponding author. E-mail: email@example.com