- Email: [email protected]
Graydon et al. provide no new evidence that forensic STR loci are functional
Forensic Science International: Genetics 4 (2010) 273–274
Contents lists available at ScienceDirect
Forensic Science International: Genetics journal homepage: www.elsevier.com/locate/fsig
Letter to the Editor Graydon et al. provide no new evidence that forensic STR loci are functional
To the editor, Graydon et al. [1] evaluated whether a 15-locus STR profile can be used to infer the ethnicity of its donor. Two major findings of their study are that ‘‘Bayesian classifiers operating on STR data perform better in distinguishing populations that are more physically different’’ and that ‘‘our results seem to indicate that there is a correspondence between STR polymorphism and physical traits, suggesting that STRs may not be just genetic ‘junk’, but may play a role in influencing phenotypic differences between people’’. Though the authors acknowledge that ‘‘genetic drift, bottlenecks, etc.’’ may have contributed to their results, this is not their primary interpretation. We disagree with the authors’ [1] assertion that forensic STR loci may be responsible for phenotypic differences among populations, and instead argue that demographic history is wholly responsible for their results. A plethora of empirical studies in human population genetics suggests that the ability to better distinguish populations that ‘‘are more physically different’’ using STRs is entirely explained by the effects of population history, rather than any association between genetic variation and phenotype. Numerous studies using protein and blood group polymorphisms [2,3], forensic VNTRs [4], STRs [5], forensic STRs [6,7], Alus [8], and SNPs [9,10] have all indicated that populations from a single continent tend to have more similar allele frequencies with other populations on that continent than with populations on different continents. In fact, FST, a measure of the difference in allele frequency between populations, is highly correlated with geographic distance between populations [3,11]. This pattern can be explained by a common origin of all humans in Africa followed by migration events and bottlenecks during the colonization of the rest of the world [11]. If the authors believe that the correlation between physical traits and forensic STR loci suggests that these loci influence physical appearance, then the other hundreds of thousands of STRs, SNPs, and Alus showing similar patterns must also be involved with influencing the same phenotypes—an unreasonable and uninformative conclusion. The degree of differentiation observed at the forensic STR loci is far lower than that would be expected if these loci had a major effect in defining physical appearance. For example, strong functional evidence suggests that a nonsynonymous SNP in SLC24A5 affects skin pigmentation in humans [12]. The Thr allele at high frequency (>95%) in European populations is rare in African and East Asian populations [12]. Similar high levels of population differentiation are seen at other loci important for skin pigmentation and hair morphology [13–15]. In contrast, the largest difference in allele frequency between a European and East Asian population for the 13 CODIS STR loci occurs for the 9 allele at TH01. This allele has frequency of 46.4% in Chinese individuals, but only 1872-4973/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.fsigen.2009.09.006
14.67% in Minnesota Caucasians (31.7% difference in frequency [16]). If instead of a particular STR allele, the overall allelic repeat number is responsible for phenotypic differences between populations, then we would expect to find substantial differences in the number of repeats at forensic STR loci across populations. However, 7 populations from throughout the world all have similar mean allele sizes [6], arguing against the influence of allelic repeat number on population-specific variation in phenotypes. While it cannot be conclusively proven that forensic STR loci have no functional effect on phenotype, the authors’ study [1] fails to provide any new evidence that they do. A weak correlation between differences in allele frequency and differences in physical traits cannot be taken as evidence of causation when population history is such a strong confounding factor. Furthermore, unlike other polymorphisms that are responsible for differences in physical appearance between individuals from different populations, forensic STR loci do not show substantial differences in allele frequency across populations. Thus, the authors’ [1] conclusion that it is easier to distinguish populations that are more different is not surprising in light of results from human population genetics over the past 20 years and should be interpreted as such. References [1] M. Graydon, F. Cholette, L.K. Ng, Inferring ethnicity using 15 autosomal STR loci— comparisons among populations of similar and distinctly different physical traits, Forensic Sci. Int. Genet. 3 (2009) 251–254. [2] L.L. Cavalli-Sforza, A. Piazza, P. Menozzi, J. Mountain, Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 6002–6006. [3] L.L. Cavalli-Sforza, P. Menozzi, A. Piazza, The History and Geography of Human Genes, Princeton University Press, Princeton, New Jersey, 1994. [4] B. Budowle, K.L. Monson, A.M. Giusti, A reassessment of frequency estimates of PvuII-generated VNTR profiles in a Finnish, an Italian, and a general U.S. Caucasian database: no evidence for ethnic subgroups affecting forensic estimates, Am. J. Hum. Genet. 55 (1994) 533–539. [5] N.A. Rosenberg, J.K. Pritchard, J.L. Weber, H.M. Cann, K.K. Kidd, L.A. Zhivotovsky, M.W. Feldman, Genetic structure of human populations, Science 298 (2002) 2381–2385. [6] R. Chakraborty, D.N. Stivers, B. Su, Y. Zhong, B. Budowle, The utility of short tandem repeat loci beyond human identification: implications for development of new DNA typing systems, Electrophoresis 20 (1999) 1682–1696. [7] D.J. Rowold, R.J. Herrera, On human STR sub-population structure, Forensic Sci. Int. 151 (2005) 59–69. [8] W.S. Watkins, A.R. Rogers, C.T. Ostler, S. Wooding, M.J. Bamshad, A.M. Brassington, M.L. Carroll, S.V. Nguyen, J.A. Walker, B.V. Prasad, P.G. Reddy, P.K. Das, M.A. Batzer, L.B. Jorde, Genetic variation among world populations: inferences from 100 Alu insertion polymorphisms, Genome Res. 13 (2003) 1607–1618. [9] A. Auton, K. Bryc, A.R. Boyko, K.E. Lohmueller, J. Novembre, A. Reynolds, A. Indap, M.H. Wright, J.D. Degenhardt, R.N. Gutenkunst, K.S. King, M.R. Nelson, C.D. Bustamante, Global distribution of genomic diversity underscores rich complex history of continental human populations, Genome Res. 19 (2009) 795–803. [10] M. Jakobsson, S.W. Scholz, P. Scheet, J.R. Gibbs, J.M. VanLiere, H.C. Fung, Z.A. Szpiech, J.H. Degnan, K. Wang, R. Guerreiro, J.M. Bras, J.C. Schymick, D.G. Hernandez, B.J. Traynor, J. Simon-Sanchez, M. Matarin, A. Britton, J. van de Leemput, I. Rafferty, M. Bucan, H.M. Cann, J.A. Hardy, N.A. Rosenberg, A.B. Singleton, Genotype, haplotype and copy-number variation in worldwide human populations, Nature 451 (2008) 998–1003. [11] S. Ramachandran, O. Deshpande, C.C. Roseman, N.A. Rosenberg, M.W. Feldman, L.L. Cavalli-Sforza, Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa, Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 15942–15947.
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Letter to the Editor / Forensic Science International: Genetics 4 (2010) 273–274
[12] R.L. Lamason, M.A. Mohideen, J.R. Mest, A.C. Wong, H.L. Norton, M.C. Aros, M.J. Jurynec, X. Mao, V.R. Humphreville, J.E. Humbert, S. Sinha, J.L. Moore, P. Jagadeeswaran, W. Zhao, G. Ning, I. Makalowska, P.M. McKeigue, D. O’donnell, R. Kittles, E.J. Parra, N.J. Mangini, D.J. Grunwald, M.D. Shriver, V.A. Canfield, K.C. Cheng, SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans, Science 310 (2005) 1782–1786. [13] A. Fujimoto, R. Kimura, J. Ohashi, K. Omi, R. Yuliwulandari, L. Batubara, M.S. Mustofa, U. Samakkarn, W. Settheetham-Ishida, T. Ishida, Y. Morishita, T. Furusawa, M. Nakazawa, R. Ohtsuka, K. Tokunaga, A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness, Hum. Mol. Genet. 17 (2008) 835–843. [14] S. Myles, M. Somel, K. Tang, J. Kelso, M. Stoneking, Identifying genes underlying skin pigmentation differences among human populations, Hum. Genet. 120 (2007) 613– 621. [15] P.C. Sabeti, P. Varilly, B. Fry, J. Lohmueller, E. Hostetter, C. Cotsapas, X. Xie, E.H. Byrne, S.A. McCarroll, R. Gaudet, S.F. Schaffner, E.S. Lander, International HapMap Consortium, Genome-wide detection and characterization of positive selection in human populations, Nature 449 (2007) 913–918.
[16] B. Budowle, B. Shea, S. Niezgoda, R. Chakraborty, CODIS STR loci data from 41 sample populations, J. Forensic Sci. 46 (2001) 453–489.
Kirk E. Lohmueller* Department of Molecular Biology and Genetics and Biostatistics and Computational Biology, 102F Weill Hall, Cornell University, Ithaca, NY, 14853, United States *Tel.:
+1 607 255 0527; fax: +1 607 255 6249 E-mail address: [email protected] 19 August 2009
Contents lists available at ScienceDirect
Forensic Science International: Genetics journal homepage: www.elsevier.com/locate/fsig
Letter to the Editor Graydon et al. provide no new evidence that forensic STR loci are functional
To the editor, Graydon et al. [1] evaluated whether a 15-locus STR profile can be used to infer the ethnicity of its donor. Two major findings of their study are that ‘‘Bayesian classifiers operating on STR data perform better in distinguishing populations that are more physically different’’ and that ‘‘our results seem to indicate that there is a correspondence between STR polymorphism and physical traits, suggesting that STRs may not be just genetic ‘junk’, but may play a role in influencing phenotypic differences between people’’. Though the authors acknowledge that ‘‘genetic drift, bottlenecks, etc.’’ may have contributed to their results, this is not their primary interpretation. We disagree with the authors’ [1] assertion that forensic STR loci may be responsible for phenotypic differences among populations, and instead argue that demographic history is wholly responsible for their results. A plethora of empirical studies in human population genetics suggests that the ability to better distinguish populations that ‘‘are more physically different’’ using STRs is entirely explained by the effects of population history, rather than any association between genetic variation and phenotype. Numerous studies using protein and blood group polymorphisms [2,3], forensic VNTRs [4], STRs [5], forensic STRs [6,7], Alus [8], and SNPs [9,10] have all indicated that populations from a single continent tend to have more similar allele frequencies with other populations on that continent than with populations on different continents. In fact, FST, a measure of the difference in allele frequency between populations, is highly correlated with geographic distance between populations [3,11]. This pattern can be explained by a common origin of all humans in Africa followed by migration events and bottlenecks during the colonization of the rest of the world [11]. If the authors believe that the correlation between physical traits and forensic STR loci suggests that these loci influence physical appearance, then the other hundreds of thousands of STRs, SNPs, and Alus showing similar patterns must also be involved with influencing the same phenotypes—an unreasonable and uninformative conclusion. The degree of differentiation observed at the forensic STR loci is far lower than that would be expected if these loci had a major effect in defining physical appearance. For example, strong functional evidence suggests that a nonsynonymous SNP in SLC24A5 affects skin pigmentation in humans [12]. The Thr allele at high frequency (>95%) in European populations is rare in African and East Asian populations [12]. Similar high levels of population differentiation are seen at other loci important for skin pigmentation and hair morphology [13–15]. In contrast, the largest difference in allele frequency between a European and East Asian population for the 13 CODIS STR loci occurs for the 9 allele at TH01. This allele has frequency of 46.4% in Chinese individuals, but only 1872-4973/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.fsigen.2009.09.006
14.67% in Minnesota Caucasians (31.7% difference in frequency [16]). If instead of a particular STR allele, the overall allelic repeat number is responsible for phenotypic differences between populations, then we would expect to find substantial differences in the number of repeats at forensic STR loci across populations. However, 7 populations from throughout the world all have similar mean allele sizes [6], arguing against the influence of allelic repeat number on population-specific variation in phenotypes. While it cannot be conclusively proven that forensic STR loci have no functional effect on phenotype, the authors’ study [1] fails to provide any new evidence that they do. A weak correlation between differences in allele frequency and differences in physical traits cannot be taken as evidence of causation when population history is such a strong confounding factor. Furthermore, unlike other polymorphisms that are responsible for differences in physical appearance between individuals from different populations, forensic STR loci do not show substantial differences in allele frequency across populations. Thus, the authors’ [1] conclusion that it is easier to distinguish populations that are more different is not surprising in light of results from human population genetics over the past 20 years and should be interpreted as such. References [1] M. Graydon, F. Cholette, L.K. Ng, Inferring ethnicity using 15 autosomal STR loci— comparisons among populations of similar and distinctly different physical traits, Forensic Sci. Int. Genet. 3 (2009) 251–254. [2] L.L. Cavalli-Sforza, A. Piazza, P. Menozzi, J. Mountain, Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 6002–6006. [3] L.L. Cavalli-Sforza, P. Menozzi, A. Piazza, The History and Geography of Human Genes, Princeton University Press, Princeton, New Jersey, 1994. [4] B. Budowle, K.L. Monson, A.M. Giusti, A reassessment of frequency estimates of PvuII-generated VNTR profiles in a Finnish, an Italian, and a general U.S. Caucasian database: no evidence for ethnic subgroups affecting forensic estimates, Am. J. Hum. Genet. 55 (1994) 533–539. [5] N.A. Rosenberg, J.K. Pritchard, J.L. Weber, H.M. Cann, K.K. Kidd, L.A. Zhivotovsky, M.W. Feldman, Genetic structure of human populations, Science 298 (2002) 2381–2385. [6] R. Chakraborty, D.N. Stivers, B. Su, Y. Zhong, B. Budowle, The utility of short tandem repeat loci beyond human identification: implications for development of new DNA typing systems, Electrophoresis 20 (1999) 1682–1696. [7] D.J. Rowold, R.J. Herrera, On human STR sub-population structure, Forensic Sci. Int. 151 (2005) 59–69. [8] W.S. Watkins, A.R. Rogers, C.T. Ostler, S. Wooding, M.J. Bamshad, A.M. Brassington, M.L. Carroll, S.V. Nguyen, J.A. Walker, B.V. Prasad, P.G. Reddy, P.K. Das, M.A. Batzer, L.B. Jorde, Genetic variation among world populations: inferences from 100 Alu insertion polymorphisms, Genome Res. 13 (2003) 1607–1618. [9] A. Auton, K. Bryc, A.R. Boyko, K.E. Lohmueller, J. Novembre, A. Reynolds, A. Indap, M.H. Wright, J.D. Degenhardt, R.N. Gutenkunst, K.S. King, M.R. Nelson, C.D. Bustamante, Global distribution of genomic diversity underscores rich complex history of continental human populations, Genome Res. 19 (2009) 795–803. [10] M. Jakobsson, S.W. Scholz, P. Scheet, J.R. Gibbs, J.M. VanLiere, H.C. Fung, Z.A. Szpiech, J.H. Degnan, K. Wang, R. Guerreiro, J.M. Bras, J.C. Schymick, D.G. Hernandez, B.J. Traynor, J. Simon-Sanchez, M. Matarin, A. Britton, J. van de Leemput, I. Rafferty, M. Bucan, H.M. Cann, J.A. Hardy, N.A. Rosenberg, A.B. Singleton, Genotype, haplotype and copy-number variation in worldwide human populations, Nature 451 (2008) 998–1003. [11] S. Ramachandran, O. Deshpande, C.C. Roseman, N.A. Rosenberg, M.W. Feldman, L.L. Cavalli-Sforza, Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa, Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 15942–15947.
274
Letter to the Editor / Forensic Science International: Genetics 4 (2010) 273–274
[12] R.L. Lamason, M.A. Mohideen, J.R. Mest, A.C. Wong, H.L. Norton, M.C. Aros, M.J. Jurynec, X. Mao, V.R. Humphreville, J.E. Humbert, S. Sinha, J.L. Moore, P. Jagadeeswaran, W. Zhao, G. Ning, I. Makalowska, P.M. McKeigue, D. O’donnell, R. Kittles, E.J. Parra, N.J. Mangini, D.J. Grunwald, M.D. Shriver, V.A. Canfield, K.C. Cheng, SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans, Science 310 (2005) 1782–1786. [13] A. Fujimoto, R. Kimura, J. Ohashi, K. Omi, R. Yuliwulandari, L. Batubara, M.S. Mustofa, U. Samakkarn, W. Settheetham-Ishida, T. Ishida, Y. Morishita, T. Furusawa, M. Nakazawa, R. Ohtsuka, K. Tokunaga, A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness, Hum. Mol. Genet. 17 (2008) 835–843. [14] S. Myles, M. Somel, K. Tang, J. Kelso, M. Stoneking, Identifying genes underlying skin pigmentation differences among human populations, Hum. Genet. 120 (2007) 613– 621. [15] P.C. Sabeti, P. Varilly, B. Fry, J. Lohmueller, E. Hostetter, C. Cotsapas, X. Xie, E.H. Byrne, S.A. McCarroll, R. Gaudet, S.F. Schaffner, E.S. Lander, International HapMap Consortium, Genome-wide detection and characterization of positive selection in human populations, Nature 449 (2007) 913–918.
[16] B. Budowle, B. Shea, S. Niezgoda, R. Chakraborty, CODIS STR loci data from 41 sample populations, J. Forensic Sci. 46 (2001) 453–489.
Kirk E. Lohmueller* Department of Molecular Biology and Genetics and Biostatistics and Computational Biology, 102F Weill Hall, Cornell University, Ithaca, NY, 14853, United States *Tel.:
+1 607 255 0527; fax: +1 607 255 6249 E-mail address: [email protected] 19 August 2009