A Genome-wide Comparison of the Functional Properties of Rare and Common Genetic Variants in Humans
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One of the longest running debates in evolutionary biology concerns the kind of genetic variation that is primarily responsible for phenotypic variation in species. Here, we address this question for humans specifically from the perspective of population allele frequency of variants across the complete genome, including both coding and noncoding regions. We establish simple criteria to assess the likelihood that variants are functional based on their genomic locations and then use whole-genome sequence data from 29 subjects of European origin to assess the relationship between the functional properties of variants and their population allele frequencies. We find that for all criteria used to assess the likelihood that a variant is functional, the rarer variants are significantly more likely to be functional than the more common variants. Strikingly, these patterns disappear when we focus on only those variants in which the major alleles are derived. These analyses indicate that the majority of the genetic variation in terms of phenotypic consequence may result from a mutation-selection balance, as opposed to balancing selection, and have direct relevance to the study of human disease.
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Whole-exome sequence data show non-synonymous substitutions are even more skewed toward low frequencies, almost certainly reflecting purifying selection.
“the finding from whole-exome sequence data that non-synonymous substitutions are even more significantly skewed towards low frequencies almost certainly reflects the operation of purifying selection32–34.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [34]
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The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
Tandem repeats finder: a program to analyze DNA sequences
Benson, G. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.2.573 · Cited by 9,374 · see citing works
Finding the missing heritability of complex diseases
Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., et al. (2009) · Nature · doi:10.1038/nature08494 · Cited by 8,336 · see citing works
Self-citationA map of human genome variation from population-scale sequencing.
The 1000 Genomes Project Consortium (2010) · Nature · doi:10.1038/nature09534 · Cited by 7,877 · see citing works
The ENCODE Project Consortium (2007) · Nature · doi:10.1038/nature05874 · Cited by 5,223 · see citing works
Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes
Siepel, A., Bejerano, G., Pedersen, J. S., Hinrichs, A. S., Hou, M., Rosenbloom, K., Clawson, H., Spieth, J., Hillier, L. W., Richards, S., et al. (2005) · Genome Research · doi:10.1101/gr.3715005 · Cited by 4,408 · see citing works
Global variation in copy number in the human genome
Redon, R., Ishikawa, S., Fitch, K. R., Feuk, L., Perry, G. H., Andrews, T. D., Fiegler, H., Shapero, M. H., Carson, A. R., Chen, W., et al. (2006) · Nature · doi:10.1038/nature05329 · Cited by 4,276 · see citing works
Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., et al. (2007) · Nature Genetics · doi:10.1038/ng1966 · Cited by 3,398 · see citing works
ON ESTIMATING THE RELATION BETWEEN BLOOD GROUP AND DISEASE
Woolf, B. (1955) · Annals of Human Genetics · doi:10.1111/j.1469-1809.1955.tb01348.x · Cited by 2,739 · see citing works
Histone modifications at human enhancers reflect global cell-type-specific gene expression
Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., et al. (2009) · Nature · doi:10.1038/nature07829 · Cited by 2,533 · see citing works
The ENCODE (ENCyclopedia Of DNA Elements) Project
(2004) · Science · doi:10.1126/science.1105136 · Cited by 2,390 · see citing works
Detection of nonneutral substitution rates on mammalian phylogenies
Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R., & Siepel, A. (2010) · Genome Research · doi:10.1101/gr.097857.109 · Cited by 2,353 · see citing works
Targeted capture and massively parallel sequencing of 12 human exomes
Ng, S. B., Turner, E. H., Robertson, P. D., Flygare, S. D., Bigham, A. W., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E. E., et al. (2009) · Nature · doi:10.1038/nature08250 · Cited by 2,030 · see citing works
Ultraconserved Elements in the Human Genome
Bejerano, G., Pheasant, M., Makunin, I., Stephen, S., Kent, W. J., Mattick, J. S., & Haussler, D. (2004) · Science · doi:10.1126/science.1098119 · Cited by 1,732 · see citing works
Are Rare Variants Responsible for Susceptibility to Complex Diseases?
Pritchard, J. K. (2001) · The American Journal of Human Genetics · doi:10.1086/321272 · Cited by 1,197 · see citing works
Uncovering the roles of rare variants in common disease through whole-genome sequencing
Cirulli, E. T., & Goldstein, D. B. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2779 · Cited by 1,136 · see citing works
Self-citationPatterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis
Halushka, M. K., Fan, J., Bentley, K., Hsie, L., Shen, N., Weder, A. B., Cooper, R., Lipshutz, R. J., & Chakravarti, A. (1999) · Nature Genetics · doi:10.1038/10297 · Cited by 1,011 · see citing works
Genetic Heterogeneity in Human Disease
McClellan, J., & King, M.-C. (2010) · Cell · doi:10.1016/j.cell.2010.03.032 · Cited by 981 · see citing works
Segmental Duplications: Organization and Impact Within the Current Human Genome Project AssemblyPreprint
Bailey, J. A., Yavor, A. M., Massa, H. F., Trask, B. J., & Eichler, E. E. (2001) · Genome Research · doi:10.1101/gr.187101 · Cited by 708 · see citing works
Siva, N. (2008) · Nature Biotechnology · doi:10.1038/nbt0308-256b · Cited by 629 · see citing works
Assessing the evolutionary impact of amino acid mutations in the human genome.
Boyko, A. R., Williamson, S. H., Indap, A. R., Degenhardt, J. D., Hernandez, R. D., Lohmueller, K. E., Adams, M. D., Schmidt, S., Sninsky, J. J., Sunyaev, S. R., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000083 · Cited by 628 · see citing works
Kryukov, G. V., Pennacchio, L. A., & Sunyaev, S. R. (2007) · The American Journal of Human Genetics · doi:10.1086/513473 · Cited by 598 · see citing works
Segmental Duplications: Organization and Impact Within the Current Human Genome Project AssemblyPreprint
Bailey, J. A. (2001) · Genome Research · doi:10.1101/gr.gr-1871r · Cited by 573 · see citing works
Annotating non-coding regions of the genome.
Alexander, R. P., Fang, G., Rozowsky, J., Snyder, M., & Gerstein, M. B. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2814 · Cited by 464 · see citing works
Classic Selective Sweeps Were Rare in Recent Human Evolution
Hernandez, R. D., Kelley, J. L., Elyashiv, E., Melton, S., Auton, A., McVean, G., 1000 Genomes Project, Sella, G., & Przeworski, M. (2011) · Science · doi:10.1126/science.1198878 · Cited by 427 · see citing works
The distribution of fitness effects of new deleterious amino acid mutations in humans.
Eyre-Walker, A., Woolfit, M., & Phelps, T. (2006) · Genetics · doi:10.1534/genetics.106.057570 · Cited by 377 · see citing works
Proportionally more deleterious genetic variation in European than in African populations
Lohmueller, K. E., Indap, A. R., Schmidt, S., Boyko, A. R., Hernandez, R. D., Hubisz, M. J., Sninsky, J. J., White, T. J., Sunyaev, S. R., Nielsen, R., et al. (2008) · Nature · doi:10.1038/nature06611 · Cited by 374 · see citing works
Shifting Paradigm of Association Studies: Value of Rare Single-Nucleotide Polymorphisms
Gorlov, I. P., Gorlova, O. Y., Sunyaev, S. R., Spitz, M. R., & Amos, C. I. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.006 · Cited by 338 · see citing works
Williamson, S., Hernandez, R. D., Fledel-Alon, A., Zhu, L., Nielsen, R., & Bustamante, C. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502300102 · Cited by 325 · see citing works
Ultraconservation identifies a small subset of extremely constrained developmental enhancers
Visel, A., Prabhakar, S., Akiyama, J. A., Shoukry, M., Lewis, K. D., Holt, A., Plajzer-Frick, I., Afzal, V., Rubin, E. M., & Pennacchio, L. A. (2008) · Nature Genetics · doi:10.1038/ng.2007.55 · Cited by 321 · see citing works
Li, Y., Vinckenbosch, N., Tian, G., Huerta‐Sánchez, E., Jiang, T., Jiang, H., Albrechtsen, A., Andersen, G., Cao, H., Korneliussen, T. S., et al. (2010) · Nature Genetics · doi:10.1038/ng.680 · Cited by 307 · see citing works
Human Genome Ultraconserved Elements Are Ultraselected
Katzman, S. J., Kern, A. D., Bejerano, G., Fewell, G. A., Fulton, L. A., Wilson, R. K., Salama, S. R., & Haussler, D. H. (2007) · Science · doi:10.1126/science.1142430 · Cited by 264 · see citing works
The Neutral Theory of Molecular Evolution in the Genomic Era
Nei, M., Suzuki, Y., & Nozawa, M. (2010) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082908-150129 · Cited by 252 · see citing works
Conserved noncoding sequences are selectively constrained and not mutation cold spots
Drake, J. A., Bird, C., Nemesh, J. C., Thomas, D. J., Newton‐Cheh, C., Reymond, A., Excoffier, L., Attar, H., Antonarakis, S. E., Dermitzakis, E. T., et al. (2005) · Nature Genetics · doi:10.1038/ng1710 · Cited by 232 · see citing works
Eyre‐Walker, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906182107 · Cited by 231 · see citing works
A flexible forward simulator for populations subject to selection and demography
Hernandez, R. D. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn522 · Cited by 208 · see citing works
Single-nucleotide evolutionary constraint scores highlight disease-causing mutations
Cooper, G. M., Goode, D. L., Ng, S. B. H., Sidow, A., Bamshad, M. J., Shendure, J., & Nickerson, D. A. (2010) · Nature Methods · doi:10.1038/nmeth0410-250 · Cited by 170 · see citing works
Genome assembly comparison identifies structural variants in the human genome
Khaja, R., Zhang, J., MacDonald, J. R., He, Y., Joseph‐George, A. M., Wei, J., Rafiq, M., Qian, C., Shago, M., Pantano, L., et al. (2006) · Nature Genetics · doi:10.1038/ng1921 · Cited by 166 · see citing works
Power of deep, all-exon resequencing for discovery of human trait genes
Kryukov, G. V., Shpunt, A., Stamatoyannopoulos, J. A., & Sunyaev, S. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812824106 · Cited by 156 · see citing works
Torgerson, D. G., Boyko, A. R., Hernandez, R. D., Indap, A. R., Hu, X., White, T. J., Sninsky, J. J., Cargill, M., Adams, M. D., Bustamante, C. D., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000592 · Cited by 136 · see citing works
Widely distributed noncoding purifying selection in the human genome
Asthana, S., Noble, W. S., Kryukov, G. V., Grant, C. E., Sunyaev, S. R., & Stamatoyannopoulos, J. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705140104 · Cited by 97 · see citing works
Analysis of Sequence Conservation at Nucleotide Resolution
Asthana, S., Абрамович, Р. М., Stamatoyannopoulos, J. A., & Sunyaev, S. R. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030254 · Cited by 82 · see citing works
Evolutionary constraint facilitates interpretation of genetic variation in resequenced human genomesPreprint
Goode, D. L., Cooper, G. M., Schmutz, J., Dickson, M. C., Gonzales, E., Tsai, M., Karra, K., Davydov, E. V., Batzoglou, S., Myers, R., et al. (2010) · Genome Research · doi:10.1101/gr.102210.109 · Cited by 80 · see citing works
High Proportions of Deleterious Polymorphisms in Constrained Human Genes
Subramanian, S. (2010) · Molecular Biology and Evolution · doi:10.1093/molbev/msq287 · Cited by 9 · see citing works
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Rare and common variants: twenty arguments
Gibson, G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3118 · Cited by 1,278 · see citing works
Battle, A., Mostafavi, S., Zhu, X., Potash, J. B., Weissman, M. M., McCormick, C., Haudenschild, C. D., Beckman, K. B., Shi, J., Mei, R., et al. (2014) · Genome Research · doi:10.1101/gr.155192.113 · Cited by 547 · see citing works
The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers
Amos, C. I., Dennis, J., Wang, Z., Byun, J., Schumacher, F. R., Gayther, S. A., Casey, G., Hunter, D. J., Sellers, T. A., Gruber, S. B., et al. (2016) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-16-0106 · Cited by 337 · see citing works
Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate dispositionPreprint
Ramsey, L. B., Bruun, G. H., Yang, W., Treviño, L. R., Vattathil, S., Scheet, P. A., Cheng, C., Rosner, G. L., Giacomini, K. M., Fan, Y., et al. (2011) · Genome Research · doi:10.1101/gr.129668.111 · Cited by 260 · see citing works
Sequencing studies in human genetics: design and interpretation
Goldstein, D. B., Allen, A. S., Keebler, J., Margulies, E. H., Petrou, S., Petrovski, S., & Sunyaev, S. R. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3455 · Cited by 254 · see citing works
Self-citationLoss-of-Function Variants in Schizophrenia Risk and SETD1A as a Candidate Susceptibility Gene
Takata, A., Xu, B., Ionita-Laza, I., Roos, J. L., Gogos, J. A., & Karayiorgou, M. (2014) · Neuron · doi:10.1016/j.neuron.2014.04.043 · Cited by 204 · see citing works
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King, E. G., Merkes, C. M., McNeil, C. L., Hoofer, S. R., Sen, Ś., Broman, K. W., Long, A. D., & Macdonald, S. J. (2012) · Genome Research · doi:10.1101/gr.134031.111 · Cited by 208 · see citing works
Zhang, W., Spector, T. D., Deloukas, P., Bell, J. T., & Engelhardt, B. E. (2015) · Genome biology · doi:10.1186/s13059-015-0581-9 · Cited by 198 · see citing works
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Gupta, P. K., Kulwal, P. L., & Jaiswal, V. (2014) · Advances in genetics · doi:10.1016/b978-0-12-800271-1.00002-0 · Cited by 155 · see citing works
Evaluating empirical bounds on complex disease genetic architecture
Agarwala, V., Flannick, J. A., Sunyaev, S. R., & Altshuler, D. (2013) · Nature Genetics · doi:10.1038/ng.2804 · Cited by 143 · see citing works
Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts
Cirulli, E. T., White, S., Read, R. W., Elhanan, G., Metcalf, W. J., Tanudjaja, F., Fath, D. M., Sandoval, E., Isaksson, M., Schlauch, K. A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14288-y · Cited by 135 · see citing works
Josephs, E. B., Lee, Y. W., Stinchcombe, J. R., & Wright, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503027112 · Cited by 122 · see citing works
What is complex about complex disorders?
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McQuillan, R., Eklund, N., Pirastu, N., Kuningas, M., McEvoy, B. P., Esko, T., Corre, T., Davies, G., Kaakinen, M., Lyytikäinen, L., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002655 · Cited by 111 · see citing works
Dewey, F. E., Pan, S., Wheeler, M. T., Quake, S. R., & Ashley, E. A. (2012) · Circulation · doi:10.1161/circulationaha.110.972828 · Cited by 100 · see citing works
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Tang, W., Fu, Y., Figueroa, J. D., Malats, N., García‐Closas, M., Chatterjee, N., Kogevinas, M., Baris, D., Thun, M. J., Hall, J. L., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr619 · Cited by 79 · see citing works
A functional motif of long noncoding RNA Nron against osteoporosis
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Capriotti, E., Nehrt, N. L., Kann, M. G., & Bromberg, Y. (2012) · Briefings in Bioinformatics · doi:10.1093/bib/bbr070 · Cited by 68 · see citing works
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Halvorsen, M., Petrovski, S., Shellhaas, R. A., Tang, Y., Crandall, L., Goldstein, D. B., & Devinsky, O. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.155 · Cited by 65 · see citing works
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Wasser, W. G., Tzur, S., Wolday, D., Adu, D., Baumstein, D. I., Rosset, S., & Skorecki, K. L. (2012) · Journal of Nephrology · doi:10.5301/jn.5000179 · Cited by 55 · see citing works
Human genomic disease variants: A neutral evolutionary explanationPreprint
Dudley, J. T., Kim, Y., Liu, L., Markov, G. J., Gerold, K., Chen, R., Butte, A. J., & Kumar, S. (2012) · Genome Research · doi:10.1101/gr.133702.111 · Cited by 52 · see citing works
McCarthy, M. J. (2018) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000215 · Cited by 47 · see citing works
Nelson, C. L., Pelak, K., Podgoreanu, M. V., Ahn, S. H., Scott, W. K., Allen, A. S., Cowell, L. G., Rude, T. H., Zhang, Y., Tong, A. Y., et al. (2014) · BMC Infectious Diseases · doi:10.1186/1471-2334-14-83 · Cited by 42 · see citing works
Sabarinathan, R., Wenzel, A., Novotny, P., Tang, X., Kalari, K. R., & Gorodkin, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0082699 · Cited by 33 · see citing works
Study of a US cohort supports the role of ZNF644 and high-grade myopia susceptibility.
Tran-Viet, K.-N., St.Germain, E., Soler, V. J., Powell, C., Lim, S.-H., Klemm, T., Saw, S., & Young, T. L. (2012) · Europe PMC (PubMed Central) · Cited by 33 · see citing works
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Quantifying harmful mutations in human populations
Subramanian, S. (2012) · European Journal of Human Genetics · doi:10.1038/ejhg.2012.68 · Cited by 27 · see citing works
microRNAs deregulation in head and neck squamous cell carcinoma
Carron, J., Torricelli, C., Silva, J. K., Queiroz, G. S. R., Ortega, M. M., Lima, C. S. P., & Lourenço, G. J. (2020) · Head & Neck · doi:10.1002/hed.26533 · Cited by 24 · see citing works
Yang, J., Wang, Z., Liu, S., Wang, W., Zhang, H., & Gui, C. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00747 · Cited by 24 · see citing works
Zhu, Q., Yan, L., Liu, Q., Zhang, C., Wei, L., Hu, Q., Preus, L. M., Clay‐Gilmour, A., Onel, K., Stram, D. O., et al. (2018) · Blood · doi:10.1182/blood-2017-11-817973 · Cited by 22 · see citing works
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Kim, J., Song, I., Jo, A., Shin, J., Cho, H., Eoff, R. L., Guengerich, F. P., & Choi, J. (2014) · Chemical Research in Toxicology · doi:10.1021/tx5002755 · Cited by 20 · see citing works
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Zhu, Q., Ge, D., Heinzen, E. L., Dickson, S. P., Urban, T. J., Zhu, M., Maia, J. M., He, M., Zhao, Q., Shianna, K. V., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.07.010 · Cited by 19 · see citing works
Self-citationHolborn, M. A., Ford, G., Turner, S., Mellet, J., van Rensburg, J., Joubert, F., & Pepper, M. S. (2022) · Genomics · doi:10.1016/j.ygeno.2022.110508 · Cited by 18 · see citing works
Matullo, G., Gaetano, C. D., & Guarrera, S. (2013) · Environmental and Molecular Mutagenesis · doi:10.1002/em.21799 · Cited by 21 · see citing works
Gu, W., Gurguis, C. I., Zhou, J. J., Zhu, Y., Ko, E.-A., Ko, J., Wang, T., & Zhou, T. (2015) · Genome Biology and Evolution · doi:10.1093/gbe/evv191 · Cited by 18 · see citing works
Stubbs, A., McClellan, E. A., Horsman, S., Hiltemann, S., Palli, I., Nouwens, S., Koning, A. H. J., Hoogland, F., Reumers, J., Heijsman, D., et al. (2012) · Journal of Clinical Bioinformatics · doi:10.1186/2043-9113-2-19 · Cited by 17 · see citing works
Song, I., Kim, E., Kim, I.-H., Park, E., Lee, K. E., Shin, J., Guengerich, F. P., & Choi, J.-Y. (2014) · Chemical Research in Toxicology · doi:10.1021/tx500072m · Cited by 17 · see citing works
Koko, M., Abdallah, M. O. E., Amin, M., & Ibrahim, M. E. (2018) · BMC Genomics · doi:10.1186/s12864-018-4433-3 · Cited by 17 · see citing works
Zhang, Q., Sahana, G., Su, G., Guldbrandtsen, B., Lund, M. S., & Calus, M. P. L. (2018) · Genetics Selection Evolution · doi:10.1186/s12711-018-0432-8 · Cited by 17 · see citing works
Copy Number Variation and Warfarin Dosing: Evaluation of CYP2C9 , VKORC1 , CYP4F2 , GGCX and CALU
Scott, S. A., Patel, M., Martis, S., Lubitz, S. A., van der Zee, S. A., Yoo, C., Edelmann, L. J., Halperin, J. L., & Desnick, R. J. (2011) · Pharmacogenomics · doi:10.2217/pgs.11.156 · Cited by 16 · see citing works
Monti, R., Rautenstrauch, P., Ghanbari, M., James, A. R., Kirchler, M., Ohler, U., Konigorski, S., & Lippert, C. (2022) · Nature Communications · doi:10.1038/s41467-022-32864-2 · Cited by 15 · see citing works
Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes
Zhu, Q., Zhang, J., Chen, Y., Hu, Q., Shen, H., Huang, R., Liu, Q., Kaur, J., Long, M. D., Battaglia, S., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32545 · Cited by 15 · see citing works
Self-citationEvidence of Inbreeding Depression on Human Height
Heliövaara, L. (2015) · Cited by 14 · see citing works
Sex differences in deleterious genetic variants in a haplodiploid social insect
Miller, S., & Sheehan, M. J. (2023) · Molecular Ecology · doi:10.1111/mec.17057 · Cited by 14 · see citing works
Six Germline Genetic Variations Impair the Translesion Synthesis Activity of Human DNA Polymerase κ
Kim, J.-K., Yeom, M., Hong, J., Song, I., Lee, Y., Guengerich, F. P., & Choi, J. (2016) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.6b00244 · Cited by 14 · see citing works
Adaptive Landscape of Protein Variation in Human Exomes
Patel, R., Scheinfeldt, L., Sanderford, M. D., Lanham, T. R., Tamura, K., Platt, A., Glicksberg, B. S., Xu, K., Dudley, J. T., & Kumar, S. (2018) · Molecular Biology and Evolution · doi:10.1093/molbev/msy107 · Cited by 11 · see citing works
Huang, Y., Lu, Y., MUES, G. I., Wang, S., Bonds, J., & D’Souza, R. N. (2013) · European Journal Of Oral Sciences · doi:10.1111/eos.12055 · Cited by 12 · see citing works
Growth of genome screening needs debate
Goldstein, D. B. (2011) · Nature · doi:10.1038/476027a · Cited by 12 · see citing works
Self-citationIntricacies in arrangement of SNP haplotypes suggest “Great Admixture” that created modern humans
Dutta, R. K., Mainsah, J., Yatskiv, Y., Chakrabortty, S., Brennan, P., Khuder, B., Qiu, S., Fedorova, L. V., & Fedorov, A. (2017) · BMC Genomics · doi:10.1186/s12864-017-3776-5 · Cited by 11 · see citing works
Zhang, J., Tang, S., Zhu, X., Li, P., Lu, J., Cong, J., Wang, L., Zhang, F., & Li, Z. (2020) · Asian Journal of Andrology · doi:10.4103/aja.aja_65_20 · Cited by 10 · see citing works
Lefèvre, J. H., Bonilla, C., Colas, C., WINNEY, B. J., Johnstone, E. C., Tonks, S., Day, T., Hutnik, K., Boumertit, A., Soubrier, F., et al. (2012) · Journal of Human Genetics · doi:10.1038/jhg.2012.99 · Cited by 11 · see citing works
Relevance and implication of genetic determinants to asthma pathophysiology
Poon, A. H., Litonjua, A. A., & Laprise, C. (2011) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0b013e32834a9540 · Cited by 10 · see citing works
Genetic intolerance analysis as a tool for protein science
Li, G., Forster-Benson, E. T. C., & Sanders, C. R. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2019.183058 · Cited by 10 · see citing works
Understanding Heritability: What it is and What it is Not
Johnson, W., Penke, L., & Spinath, F. M. (2011) · European Journal of Personality · doi:10.1002/per.835 · Cited by 9 · see citing works
Leveraging Prior Information to Detect Causal Variants via Multi-Variant Regression
Long, N., Dickson, S. P., Maia, J. M., Kim, H. S., Zhu, Q., & Allen, A. S. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003093 · Cited by 8 · see citing works
Self-citationModel teleosts for the study of idiopathic-type spinal curvatures: potential biomedical applications
Gorman, K. F., Pohl, K., Ali, F., Bandwait, K., & Breden, F. J. (2012) · Journal of Applied Ichthyology · doi:10.1111/j.1439-0426.2012.01982.x · Cited by 7 · see citing works
Jiang, D., & Wang, M. (2018) · Biostatistics & Epidemiology · doi:10.1080/24709360.2018.1529346 · Cited by 6 · see citing works
Tenenbaum, J. D., Shah, N. H., & Altman, R. B. (2013) · Springer eBooks · doi:10.1007/978-1-4471-4474-8_25 · Cited by 6 · see citing works
Zhang, G. (2015) · Current Genetic Medicine Reports · doi:10.1007/s40142-015-0083-9 · Cited by 5 · see citing works
Zhang, B.-L., Chen, Y., Zhang, Y., Qiao, Y., Wu, Y., Zhang, Y., Lu, Y., You, X., Li, Y., Huang, H.-D., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63747-x · Cited by 4 · see citing works
Id‐Lahoucine, S., Cánovas, Á., Legarra, A., & Casellas, J. (2023) · Journal of Dairy Science · doi:10.3168/jds.2022-23062 · Cited by 4 · see citing works
Genetic variations and associated pathophysiology in the management of epilepsy
Dibbens, L. M., & Mulley (2011) · The Application of Clinical Genetics · doi:10.2147/tacg.s7407 · Cited by 4 · see citing works
Large Genomic Region Free of GWAS-Based Common Variants Contains Fertility-Related Genes
Qiu, R., Chen, C., Jiang, H. F., Shen, L., Wu, M., & Liu, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061917 · Cited by 3 · see citing works
He, Y., Luo, J., Chen, Y., Zhou, X., Yu, S., Jin, L., Xiao, X., Jia, S., & Liu, Q. (2017) · Molecular Genetics and Genomics · doi:10.1007/s00438-017-1377-2 · Cited by 3 · see citing works
Introduction to GWAS and MutMap for identification of genes/QTL using next-generation sequencing
Yano, K., Ohmori, Y., & Fujiwara, T. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-811308-0.00017-x · Cited by 2 · see citing works
Id‐Lahoucine, S., Casellas, J., Lu, D., Sargolzaei, M., Miller, S. P., & Cánovas, Á. (2023) · Scientific Reports · doi:10.1038/s41598-023-37710-z · Cited by 2 · see citing works
The Genetic Makeup of Azoreans Versus Mainland Portugal Population
Castelo, C., & Mota-Vieir, L. (2011) · InTech eBooks · doi:10.5772/25238 · Cited by 2 · see citing works
Nutrigenomics in Disease Prevention and Management
Kaila, N. H. J., Halami, P. M., & Muthukumar, S. (2026) · Springer eBooks · doi:10.1007/978-3-032-12415-9_4 · Cited by 1 · see citing works
The Genome-Wide Association Study
Li, H., Tsuchimoto, S., Harada, K., & Fukui, K. (2017) · Compendium of plant genomes · doi:10.1007/978-3-319-49653-5_10 · Cited by 1 · see citing works
Pervasive System Biology for Active Compound Valorization in Jatropha
Carels, N., Magalhães, M., Lima, C. R., Bahadur, B., & de Menezes, M. A. (2019) · Springer eBooks · doi:10.1007/978-981-13-3104-6_12 · Cited by 1 · see citing works
Pharmacogenetics and Pharmacogenomics
Nebert, D. W., & Vesell, E. S. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-383834-6.00023-9 · Cited by 1 · see citing works
Mehboob, M. Z., Hamid, A., Kumar, J. S., & Lei, X. (2025) · BMC Cancer · doi:10.1186/s12885-025-13685-0 · Cited by 1 · see citing works
Genetic Risk Factors for Alzheimer’s Disease
Combarros, O. (2014) · Springer eBooks · doi:10.1007/978-1-4471-6380-0_4 · Cited by 1 · see citing works
Tenenbaum, J. D., Shah, N. H., & Altman, R. B. (2021) · Springer eBooks · doi:10.1007/978-3-030-58721-5_26 · Cited by 1 · see citing works
Generalizing from sequencing studiesPreprint
King, C. R., Rathouz, P. J., & Nicolae, D. L. (2013) · arXiv (Cornell University) · Cited by 1 · see citing works
Correction: Multiple Regression Methods Show Great Potential for Rare Variant Association Tests
Xu, C., Ladouceur, M., Dastani, Z., Richards, J. B., Ciampi, A., & Greenwood, C. M. T. (2013) · PLoS ONE · doi:10.1371/annotation/df00a9fb-1465-4178-9e39-aa21f7e04c4c · Cited by 1 · see citing works
Genome-Wide Analyses of HIV-1 Host Genetics
Pelak, K. (2012) · DukeSpace (Duke University)
The Mutational Spectrum of Neurodevelopmental Disorders
Merner, N. D., Dion, P. A., & Rouleau, G. A. (2015) · Wiley eBooks · doi:10.1002/9781118524947.ch3
Molecular Genetics of Coeliac Disease
Mistry, V., & van Heel, D. A. (2011) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0022476
VPA: an R tool for analyzing sequencing variants with user-specified frequency pattern
Hu, Q., Wang, D., Li, Y., Zhao, H., & Liu, S. (2012) · BMC Research Notes · doi:10.1186/1756-0500-5-31
The Genetic Mechanisms Underlying Human Obesity
Clark, S. J. (2012) · doi:10.25560/11607
Sezerman, O. U., Bozkurt‐Yozgatli, T., & Isleyen, F. S. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.92738
Monti, R., Rautenstrauch, P., Ghanbari, M., James, A. R., Ohler, U., Konigorski, S., & Lippert, C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.27.444972
Selection against Amino Acid Replacements in Human Proteins
Subramanian, S. (2013) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0020859.pub2
Yu, D., Koslovsky, M. D., Steiner, M. C., Mohammadi, K. A., Zhang, C., & Swartz, M. D. (2024) · PLoS ONE · doi:10.1371/journal.pone.0314502
Kouche, S. E., & Meyre, D. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156353
Quast, C. (2014) · Electronic Theses of LMU Munich (Ludwig-Maximilians-Universität München) · doi:10.5282/edoc.16546
- Authors
- Zhu, Q., Ge, D., Maia, J. M., Zhu, M., Petrovski, S., Dickson, S. P., Heinzen, E. L., Shianna, K. V., & Goldstein, D. B.
- Affiliations
- Duke University (US)
- Corresponding author
- Goldstein, David B.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 88
- Issue
- 4
- Pages
- 458-468
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3071924
- OpenAlex
- W2085967808
- Cited by
- 96
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 12 · 2012: 20
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, Santa Cruz
- National Institute of Mental Health (RC2MH089915)
- National Institute of Allergy and Infectious Diseases (U19AI067854, AI-067854, U01AI067854)
- National Institute of Neurological Disorders and Stroke (RC2NS070344)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- rare variants, common genetic variants, allele frequency, functional variants, mutation-selection balance, balancing selection, derived alleles, phenotypic variability, non-coding variants, coding variants, human disease
- MeSH terms
- Alleles, Gene Frequency, Genes, Regulator, Humans, Models, Genetic, Mutation, Phenotype, Selection, Genetic, Genetic Variation, Genome, Human, Conserved Sequence, Evolution, Molecular, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study
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