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PERSPECTIVES GENETICS Human Genetic Variation, Shared and Private Analyses of rare and common variants in the genome reveal another layer of human genetic variation within and among populations. Ferran Casals and Jaume Bertranpetit CREDIT: C. BICKEL/SCIENCE T he development of agriNot all loss-of-function variants culture and livestock in will have the same phenotypic the transition from the effect, with some better tolerated Paleolithic to the Neolithic era because of genetic and functional some 10,000 years ago heralded redundancy. Because the relationa demographic explosion in our ship between a mutation and its species that is still ongoing today. functional effect is not straightParadoxically, this rapid popuforward, more sophisticated prelation growth, made possible by dictive tools are needed that conimproved living conditions, may sider aspects such as the role and be responsible for an excess of position in gene interaction netdamaging variants in our genome. works and the final phenotypic Two papers in this issue, by Teneffect given possible alternative nessen et al. (1) on page 64 and pathways that may hide the deleNelson et al. (2) on page 100, terious or lethal effect of a mutareport deep-resequencing analtion. Predictions will have to conyses of all the human proteinsider the effect on organisms, not coding genes (the exome) and of only on protein structure. 202 genes that are putative drug The studies by Tennessen et targets in thousands of individual. and Nelson et al. sound two als, respectively. The studies show important warnings regarding that most of the genetic variants the experimental design of assooccur at very low frequencies in ciation analyses for rare varihuman populations, which accu- Human genetic variation. Proportion of shared and unshared (private) variants ants: Large samples sizes will mulate an excess of potentially between the African-American and the European-American populations [data be required (sometimes too large from (1)]. harmful mutations. for actual studies), and replicaUntil recently, the snapshot tion across populations will be of human genetic variation was mainly and function (1–6) and, hence, are poten- limited, as most of the rare variants will be restricted to variants at frequencies above tially involved in disease. The proportion of specific to each population. Genome-wide ~1 to 5%, because of technological and cost rare, functional nucleotide changes greatly association studies, which include up to sevlimitations. As such, medical and population exceeds the expected number predicted by eral million polymorphic positions throughgenetics studies have been based on infor- classical population genetics analysis. This out the genome, have provided insight into mation derived from common variants called seems to be due to the inefficiency of natural complex disorders by accounting for up to polymorphisms (and is the reason that stud- selection in removing these variants because 10 to 20% of their genetic component (9). ies have focused on single-nucleotide poly- of the dramatic population growth in the last The rest of the heritability remains to be morphisms, or SNPs). Now, next-genera- few thousand years (3, 4), which could lead explained, and rare variants are among the tion DNA sequencing technologies allow to an important reduction of fitness in future alternative proposed factors (10, 11). Conthe analysis of thousands of samples and societies (7). tingency tables comparing the allele frethe characterization of less frequent genetic This mutational burden in the population quency in control groups versus patients do variation. This variation is younger than that is also seen at the individual level. Each per- not have enough statistical power because studied previously and harbors informa- son carries some 35 nonsense substitutions of the low frequency of rare variants, even tion about more recent demographic events: that disrupt the formation of functional pro- for very large samples. Much effort is being There is an excess of rare variants (at a fre- teins. This number increases to 100 when all invested in developing statistical tools to quency q ≤ 0.5%) in relation to the exist- the loss-of-function mutations are consid- check for association of rare variants with ing models due to the explosive population ered, with 20 substitutions in a homozygous complex disease, usually considering an growth of recent epochs (1–6). state (8), while 10 to 15% of the individuals aggregate effect of rare variants (12), which Low-frequency variants are enriched are compound heterozygotes for nonsense is of statistical interest but has poor biomedifor changes that alter protein sequence variants in at least one gene. These figures cal interpretation. Thus, samples comprising raise the question of predicting the func- thousands of individuals still have reduced tional impact of DNA sequence variants not statistical power even to detect large genetic IBE–Institute of Evolutionary Biology (UPF-CSIC), Univeronly at the local level of protein structure and effects, leading to the need for even bigger sitat Pompeu Fabra, Barcelona, Catalonia, Spain. E-mail: [email protected] function but also at the level of the organism. sample sizes (1). www.sciencemag.org SCIENCE VOL 337 6 JULY 2012 Published by AAAS 39 PERSPECTIVES Replication of the association across populations is crucial in genetic studies. In general, allele frequencies for common variants do not differ significantly across populations, especially within the same continent (13). But this picture becomes different for rare variants (14), as many will be population-specific. The sharing of rare variants is reduced to about 10 to 30% among populations in different continents (see the figure) and to 70 to 80% among populations in the same continent (1, 2). Consequently, those variants are more prone to show geographic stratification (due not to a predisposition to disease but to geographical differences), which may lead to false-positives (1, 15) and predicts a lack of replication across populations. Reduced allele sharing across populations points out the need for population-specific catalogs of variants, as well as careful collection of information about ancestry and correction for stratification. The genetic analysis of complex diseases through the comparison of cases and controls, which has long been a widely used study design, may be approaching a conundrum that may not be solved just by increasing sample sizes and doing the most detailed type of analysis, the comparison of gene sequences. Studies based on whole-genome sequences in thousands of individuals over the next few years should help to clarify the role of rare variants and their distribution in the genome and across human populations; such studies will represent an analytical and a computational challenge. But first, a better understanding of the functional impact of non–protein-coding variation, including regulatory regions, is needed as well as the development of tools to carefully functionally annotate genome variants. These steps would allow prioritizing of candidate variants and genes, both in the filtering approaches for rare Mendelian diseases and in the assignment of different weights in aggregate tests for complex disease studies and the interpretation of personalized genomic risk profiles. Ulti- mately, we will need to go back to basic biology to link genome variation and phenotypes. References and Notes 1. J. A. Tennessen et al., Science 337, 64 (2012); 10.1126/ science.1219240. 2. M. R. Nelson et al., Science 337, 100 (2012); 10.1126/ science.1217876. 3. A. Coventry et al., Nat. Commun. 1, 131 (2010). 4. A. Keinan, A. G. Clark, Science 336, 740 (2012). 5. Y. Li et al., Nat. Genet. 42, 969 (2010). 6. G. T. Marth et al., Genome Biol. 12, R84 (2011). 7. M. Lynch, Proc. Natl. Acad. Sci. U.S.A. 107, 961 (2010). 8. D. G. MacArthur et al., Science 335, 823 (2012). 9. P. M. Visscher et al., Am. J. Hum. Genet. 90, 7 (2012). 10. G. Gibson, Nat. Rev. Genet. 13, 135 (2011). 11. T. A. Manolio et al., Nature 461, 747 (2009). 12. J. Asimit, E. Zeggini, Annu. Rev. Genet. 44, 293 (2010). 13. G. Barbujani, A. Magagni, E. Minch, L. L. Cavalli-Sforza, Proc. Natl. Acad. Sci. U.S.A. 94, 4516 (1997). 14. S. Gravel et al., Proc. Natl. Acad. Sci. U.S.A. 108, 11983 (2011). 15. I. Mathieson, G. McVean, Nat. Genet. 44, 243 (2011). Acknowledgment: F.C. holds a BP-DGR fellowship from AGAUR (Generalitat de Catalunya). 10.1126/science.1224528 PHYSICS Two Atoms Announce Their Long-Distance Relationship The quantum entanglement of two atoms 20 m apart, verified by a secondary process, can enable long-distance quantum communications. Jürgen Volz and Arno Rauschenbeutel 冷Ψ – 冭 Vienna Center for Quantum Science and Technology, Atominstitut, Vienna University of Technology, Stadionallee 2, 1020 Wien, Austria. E-mail: [email protected]; arno.rauschenbeutel@ tuwien.ac.at 40 Entangled Atom 1 Atom 2 6 JULY 2012 VOL 337 SCIENCE www.sciencemag.org Published by AAAS an entangled two-photon Bell state like |Ψ–〉 is detected, the atoms are also projected onto an entangled state. The success of the process is signaled by the “click” of the Bell state detector. CREDIT: P. HUEY/SCIENCE E ntanglement is a counterintuitive communication, the generation of entangle- many advantages, such as the exponential property of quantum mechanics that ment over macroscopic distances must be speed-up of certain algorithms (2) or the posputs it at odds with our classical view “heralded”—a separate signal must verify sibility of detecting, with certainty, the presof the world. For example, an entangled state that the entangled state was created. On page ence of an eavesdropper in a communicaof two photons can be created such that each 72 of this issue, Hofmann et al. (1) describe tion channel (3). For this purpose, informasingle photon is unpolarized—it will always the accomplishment of this goal with two tion is encoded in “quantum bits” (qubits)— pass through a polarization analyzer (e.g., a individual atoms held in laser traps and sepa- the basic quantum information carriers that filter) with 50% probability no matter how rated by a distance of 20 m. can, in contrast to classical bits, also exist in the analyzer is oriented. However, once one Quantum-based communication and a superposition of the logical states “0” and of the two photons has passed through its information-processing schemes promise “1”. Experiments making use of these effects analyzer, the second photon becomes Telling on entangled atoms. A Optical fiber Optical fiber polarized, and its orientation will then The experimental sequence Bell state Laser Laser be orthogonal to the first. Such effects measurement developed by Hoffman et al. pulse pulse are not only interesting from a fundafor “heralding” the entanglemental point of view: If the two entanment of distant atoms is illusgled particles are shared between two trated. (A) Each atom is excited Photon 1 Photon 2 distant parties, the perfect quantum by a short laser pulse and emits a photon that is entangled with Atom 1 Atom 2 correlations can be used to realize the final atomic state. These a so-called quantum channel over photons are guided through which quantum information can be Optical fiber Optical fiber optical fibers to a Bell state B transmitted. However, to exploit these Click! measurement setup. (B) Once schemes in long-distance quantum