Mutational analysis of 33 autosomal short tandem repeat (STR) loci in southwest Chinese Han population based on trio parentage testing

Forensic Science International: Genetics 23 (2016) 86–90

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Mutational analysis of 33 autosomal short tandem repeat (STR) loci in southwest Chinese Han population based on trio parentage testing Bo Jina,b,1 , Qin Sua,1, Haibo Luoa , Yingbi Lia , Jin Wua , Jing Yana , Yiping Houa , Weibo Lianga,* , Lin Zhanga,* a b

Department of Forensic Genetics, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China Department of Forensic Medicine, North Sichuan Medical College, Nanchong 637000, PR China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 January 2016 Received in revised form 17 February 2016 Accepted 28 March 2016 Available online 28 March 2016

Mutation rates and 95% CI of 33 short tandem repeat (STR) loci (D1S2142, D2S1338, D2S441, D3S1358, D3S1754, D5S818, D6S1043, D7S3048, D7S820, D8S1132, D8S1179, D10S1248, D11S2368, D12S391, D13S1492, D13S317, D13S325, D14S306, D15S659, D16S539, D18S1364, D18S51, D19S433, D20S161, D21S11, D22GATA198B05, CSF1PO, FGA, Penta D, Penta E, TH01, TPOX, and vWA) were investigated through more than 424,000 parent-child meiotic transfers obtained from 10636 trios parentage testing cases in southwest Chinese Han population. Overall, 297, including 292 single-step, 4 double-step and 1 triple-step mutation events were observed. The average mutation rate was 0.70  10 3. Most of the locus-specific mutation rates (varied from 0.20  10 3 to 1.96  10 3) were lower than the other datasets (p < 0.05). Mutations of 7 loci are reported for the first time. Mutation rates varied with population from different ethnicities and geographical regions. There was no significant difference between mutation expansion and contraction (1.04:1). Paternal origin mutations occurred more frequently than maternal origin ones (5.02:1). In addition, mutation rates indicated positive correlation with the expected heterozygosity (He) and geometric mean of longest run of perfect repeats (LRPR), respectively. Short alleles showed a trend toward mutation gain while long alleles trended toward mutation loss. A credible forensic dataset for locus-specific mutation rates of 33 loci has been established based upon strict inclusion criteria of large-sized parents/child-trio cases. ã 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Short tandem repeats (STRs) Southwest Chinese Han Population genetics Mutations

1. Introduction Short tandem repeats (STRs), abundant in human genome, are inherited in a relatively stable manner with high polymorphism and heterozygosity. They are the most widely used genetic markers in human identity testing including population genetics, linkage analysis, forensic casework, individual identification and parentage testing [1,2]. The most commonly used STR loci are the Combined DNA Index System (CODIS) including D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, CSF1PO, FGA, TH01, TPOX and vWA, selected by the United States Federal Bureau of Investigation (FBI) in 1997 [3]. STR loci, also known as microsatellites, have relatively high mutation rates due to their molecular architecture [4]. If it occurred in parentage testing,

* Corresponding authors. E-mail addresses: [email protected] (W. Liang), [email protected] (L. Zhang). 1 These authors contributed equally to this work, and were considered as co-first author. http://dx.doi.org/10.1016/j.fsigen.2016.03.009 1872-4973/ ã 2016 Elsevier Ireland Ltd. All rights reserved.

mutation(s) should be taken into account when calculating the cumulative paternity index (CPI), sometimes additional STR loci should be detected to get enough DNA intelligence, especially in complex or deficient cases [5–7]. However, the more STR loci are tested, the greater probability of mutations could occur [8]. Thus, credible information of mutation rates of STR loci represents an important approach for interpretation of paternity. In this study, we report the mutations of 33 STRs, including 13 CODIS STRs and 20 additional loci in the southwest Chinese Han population. 2. Materials and methods 2.1. Population and samples We selected 10636 trio parentage testing cases consecutively from the southwest Chinese Han ethnic population at the Department of Forensic Genetics, West China School of Preclinical and Forensic Medicine, Sichuan University, Sichuan Forest Forensic Center and Forensic Center of Chengdu Public Security Bureau, Sichuan, China during 2002–2014. All parental pairs proclaimed

B. Jin et al. / Forensic Science International: Genetics 23 (2016) 86–90

absence of consanguinity and volunteered for this study based upon Informed Consent. The CPI of each case was over 10,000 to confirm the parenthood based on the STRs. 2.2. DNA extraction, amplification and genotyping The Chelex-1001 protocol [9] was used to extract genomic DNA from peripheral blood or buccal cotton swab samples. All core CODIS loci and D1S2142, D2S1338, D2S441, D3S1754, D6S1043, D7S3048, D8S1132, D10S1248, D11S2368, D12S391, D13S1492, D13S325, D14S306, D15S659, D18S1364, D19S433, D20S161, D22GATA198B05, Penta D, and Penta E, were amplified using multiplex PCR system PowerPlex 18D (Promega, Madison, Wisconsin, USA), PowerPlex 21 (Promega, Madison, Wisconsin, USA), and Goldeneye 20A kit (Peoplespot Incorporation, Beijing, China) for cases prior to Dec 31, 2012, AGCU Expressmarker 22 kit (AGCU ScienTech Incorporation, Wuxi, Jiangsu, China) for cases after Jan 1 2013 and STRtyper-10F/G kit (Codon Incorporation, Zhuhai, Guangdong, China) according to their manufacturers’ instructions. 6 loci, D1S2142, D3S1754, D13S1492, D14S306, D15S659 and D20S161 which were not included in any kits, were treated followed the technique described by Li et al. [10]. PCR products were electrophoresed on an ABI PRISM 310/3130 Genetic Analyzers (Applied Biosystems, Foster City, CA, USA). Original data were analyzed with Gene Mapper ID v3.2 software (Applied Biosystems). Allele assignment was determined by comparison with kit-specific referenced ladders respectively.

87

2.3. Mutation testing A mutation was presumed when there was an isolated parent (s)/child mismatch at an STR locus, which appeared as Mendelian inconsistency [4]. Cases with one or two assumed STRs mutations were re-tested with the same kit and STRtyper-10F/G kit with additional STR markers to confirm the events. If the final CPI was over 100,000 (excluding inconsistent loci) with or without additional STRs, mutation(s) could be confirmed. The parental origin and the number of mutational steps were ascertained according to Brinkmann’s and Weber’s definition [4,11]. Mutations were evaluated after eliminating the null/silent alleles, which were assumed in cases of single inconsistency between the homozygous parents and children at an STR locus when the other loci were consistent with that of parents [12]. All null alleles were reconfirmed by repeated genotyping with the same kit. 2.4. Quality control Experiments were conducted in the Forensic Genetic Laboratory, Department of Forensic Genetics, West China School of Preclinical and Forensic Medicine, Sichuan University, Sichuan Forest Forensic Center; and Forensic Center of Public Security Bureau, Chengdu, Sichuan, China, which is accredited to ISO 17025. The study was conducted based on the recommendations of Morling et al. [13].

Table 1 Mutation rate and 95% CI observed at 33 STR loci in the Han population from southwest China. Paternal

Maternal

Locus

N.M

N.T

M.R  10

D1S2142 D2S1338 D2S441 D3S1358 D3S1754 D5S818 D6S1043 D7S3048 D7S820 D8S1132 D8S1179 D10S1248 D11S2368 D12S391 D13S1492 D13S317 D13S325 D14S306 D15S659 D16S539 D18S1364 D18S51 D19S433 D20S161 D21S11 CSF1PO FGA GATA198B05 Penta D Penta E TH01 TPOX vWA

1 9 5 11 1 6 7 0 6 3 11 1 4 24 1 9 2 1 1 6 3 17 3 0 10 9 37 3 5 22 1 1 21

662 6637 4292 10,560 1477 10,568 7899 2113 10,532 2097 10,560 4300 2114 9409 1229 9654 2101 1200 1230 10,486 2132 10,362 6598 1536 10,341 10,493 10,481 2082 9218 9204 10,230 10,085 10,553

1.51 1.36 1.16 1.04 0.68 0.57 0.89 0.00 0.57 1.43 1.04 0.23 1.89 2.55 0.81 0.93 0.95 0.83 0.81 0.57 1.41 1.64 0.45 0.00 0.97 0.86 3.53 1.44 0.54 2.39 0.10 0.10 1.99

Total

241

212,435

1.13

3

95% CI  10

3

3

95% CI  10

3

U

Total

N.M

N.M

N.T

M.R  10

3

N.M

N.T

M.R  10

0.04–8.39 0.62–2.57 0.38–2.72 0.52–1.86 0.02–3.77 0.21–1.24 0.36–1.83 0.00–1.74 0.21–1.24 0.30–4.18 0.52–1.87 0.01–1.30 0.52–4.84 1.64–3.79 0.02–4.53 0.43–1.77 0.12–3.43 0.02–4.63 0.02–4.52 0.21–1.25 0.29–4.11 0.96–2.63 0.09–1.33 0.00–2.40 0.46–1.78 0.39–1.63 2.49–4.86 0.30–4.21 0.18–1.27 1.50–3.62 0.00–0.54 0.00–0.55 1.23–3.04

0 1 1 0 0 2 3 2 0 2 0 1 1 4 1 2 0 0 0 2 0 1 2 1 7 0 4 0 0 4 4 2 1

662 6637 4292 10,560 1477 10,568 7899 2113 10,532 2097 10,560 4300 2114 9409 1229 9654 2101 1200 1230 10,486 2132 10,362 6598 1536 10,341 10,493 10,481 2082 9218 9204 10,230 10,085 10,553

0.00 0.15 0.23 0.00 0.00 0.19 0.38 0.95 0.00 0.95 0.00 0.23 0.47 0.43 0.81 0.21 0.00 0.00 0.00 0.19 0.00 0.10 0.30 0.65 0.68 0.00 0.38 0.00 0.00 0.43 0.39 0.20 0.09

0.00–5.56 0.00–0.84 0.01–1.30 0.00–0.35 0.00–2.49 0.02–0.68 0.08–1.11 0.11–3.41 0.00–0.35 0.12–3.44 0.00–0.35 0.01–1.30 0.01–2.63 0.13–1.09 0.02–4.53 0.03–0.75 0.00–1.75 0.00–3.07 0.00–2.99 0.02–0.69 0.00–1.73 0.00–0.54 0.04–1.09 0.02–3.62 0.27–1.39 0.00–0.35 0.10–0.98 0.00–1.77 0.00–0.40 0.12–1.11 0.11–1.00 0.02–0.72 0.00–0.53

0 0 0 2 0 0 0 0 1 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 1

1 10 6 13 1 8 10 2 7 5 11 2 5 29 2 12 2 1 1 8 3 18 5 1 18 9 41 3 5 26 5 4 23

1324 13,274 8584 21,120 2954 21,136 15,798 4226 21,064 4194 21,120 8600 4228 18,818 2458 19,308 4202 2400 2460 20,972 4264 20,724 13,196 3072 20,682 20,986 20,962 4164 18,436 18,408 20,460 20,170 21,106

0.76 0.75 0.70 0.62 0.34 0.38 0.63 0.47 0.33 1.19 0.52 0.23 1.18 1.54 0.81 0.62 0.48 0.42 0.41 0.38 0.70 0.87 0.38 0.33 0.87 0.43 1.96 0.72 0.27 1.41 0.24 0.20 1.090

0.02–4.20 0.36–1.39 0.26–1.52 0.33–1.05 0.01–1.88 0.16–0.75 0.30–1.16 0.06–1.71 0.13–0.68 0.39–2.78 0.26–0.93 0.03–0.84 0.38–2.76 1.03–2.21 0.10–2.94 0.32–1.09 0.06–1.72 0.01–2.32 0.01–2.26 0.16–0.75 0.15–2.05 0.51–1.37 0.12–0.88 0.01–1.81 0.52–1.38 0.20–0.81 1.40–2.65 0.15–2.10 0.09–0.63 0.92–2.07 0.08–0.57 0.05–0.50 0.69–1.63

1.00–1.29

48

212,435

0.23

0.16–0.30

8

297

424,870

0.70

0.62–0.78

N.M: number of mutations, N.T: number of transmissions, M.R: mutation rate, U: mutation origin was unassigned.

95% CI  10

3

88

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2.5. Data analysis The mutation rates with 95% confidence intervals (CI) were calculated based on the description of Lu et al. [14]. Expected heterozygosity (He) was estimated with the Arlequin Ver 3.5.1.3 (http://cmpg.unibe.ch/software/arlequin3/). The data in this study were compared with other reports through Pearson Chi-Square test using the SPSS 22.0 software (SPSS Incorporation, Chicago, Illinois, USA). The relevancy of each locus mutation rate and the He, and geometric mean of the size of the longest run of perfect repeats (LRPR) were calculated [15] using SPSS 22.0. Other statistical tests are described in the article. A p value < 0.05 suggested a statistical significant between two variables. 3. Results and discussion Hans represent the major ethnicity constituting 90% of the 1.4 billion Chinese. Mutations of STR loci of several regions in China have been reported in previous studies [14,16,17], while some of the datasets were limited due to different inclusion criteria involving ethnicities and case types. In this study, all the 10,636 cases were collected from Han population located in southwest China (mostly from Sichuan, some from Yunnan, Guizhou, Xizang, data not shown) and only parents-child-trio cases were counted. 3.1. Overview In 10,636 cases, allelic transmissions of 33 STR loci exceeded 500 per locus and approximately 425,000 in total. The mutation rate and 95% CI of each locus are shown in Table 1. A total of 297 mutation events in 296 cases (2.78% compared with 10636), including 295 cases with one-locus and 1 case with two-locus mismatch were found. Genotypes of parents and children, and steps, origin and direction of 297 mutations at 33 loci are shown in Table S1. The average mutation rate across all the 33 loci was 0.70  10 3, which was significantly lower than other reports (p < 0.05) [16–18] even after excluding non-CODIS loci and/or loci only reported in this study (Table S2 and Table S3). The observed locus-specific mutation rates ranged from 0.20  10 3 (TPOX) to 1.96  10 3 (FGA), which was in the range reported by Qian et al.

[17] in all the Chinese (reported mutation rates of 0.11 10 3 4.01 10 3 per locus per gamete per generation). FGA had the highest total and paternal origin mutation rate, while D21S11 indicated the highest maternal origin mutation rate. No mutation was found in D2S1772 through 4236 allele transfers (not shown in Table 1). Until now, mutation of locus D10S1248 has been reported only by Yuan et al. [19] with a limited sample size (1 mutation over 238 allele transfers), while 2 mutations over 8600 allele transfers were found in this study. Mutations of loci D1S2142, D2S441, D3S1754, D13S1492, D14S306, D15S659, and D20S161 have never been reported in parentage testing cases to our knowledge. CODIS are the most world-widely used forensic genetic markers. We compared locus-specific mutation rates and 95% CI of the 13 core loci in this study (Mongoloid) with other reported data representing various ethnicities in China (Mongoloid) [17], Brazil (Caucasian) [18], Germany (Caucasian) [20] and Nigeria (Negroid) [21] (Table S2). In general, most of the loci in this study demonstrated statistically lower mutation rates when comparing with others (p < 0.05). In addition, to evaluate the impact of case type (trios or duos) and regional population on mutation, we compared locus-specific mutation rates and 95% CIs of 19 loci in this study with south Chinese Han [16] and north Chinese (not only Han) population [17] (Fig. 1 and Table S3). 6 loci in this study indicated significantly lower mutation rates (p < 0.05), and other 13 loci showed various inconsistency across three datasets. The combined data from these three regions of China indicated an overall average mutation rate of 1.02  10 3. According to what we found above, the ethnicities, geographical regions from where the population samples were collected and case types (trios or duos) may impact the mutation rates over these datasets. 3.2. Mutation steps and gender origin 292 single-step, 4 double-step and 1 triple-step mutations were observed (Table S4). The ratio between one-step changes and greater than 1-step changes was similar to another report [16]. The finding that the vast majority of mutations were single-step changes (98.3%) was theoretically illustrated with a hypothesis known as the stepwise mutation model (SMM) [22,23]. Excluding 49 mutations, for which direction could not be assigned, the ratio

Fig. 1. Mutation rates and 95% CI of 19 autosomal STRs in Southwest, South and North Chinese.

B. Jin et al. / Forensic Science International: Genetics 23 (2016) 86–90

89

-4.50

-4.00

Log Mutation rate

-3.50

-3.00

-2.50

-2.00

-1.50

-1.00 0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

Heterozygosity Fig. 2. Correlation between the logarithm of mutation rate and heterozygosity.

between single-repeat gains and losses was 124:119 (p > 0.05, no statistical difference), which supported the explanation of replication slippage [24]. The ratio was similar to the reports from A.M. Leopoldino [15] and A.C. Mardini et al. [18]. There were 49 unassigned mutations (Table S1), nevertheless, according to the ratio between gain and loss in the 243 mutations, it was reasonable to believe that the unassigned 49 mutations showed similar distribution. Except 8 unassigned events, there were 241 paternal and 48 maternal mutations, which were significantly different (p < 0.05). The ratio between paternal/maternal mutations in this study (5.02:1) was highly consistent with other reports [18].

Mutations occur more frequently in males than in females, which could be attributed to different numbers and types of cell division in germ-cell genesis [4]. 3.3. Factors influencing mutation In addition to geographic and ethnic impacts as described above, the STR mutation rates are affected by heterozygosity [14], length and structure of the repeat, parental age, allele size [4], composition of flanking region, and degree of methylation [25]. Based on the data calculated from 21,272 unrelated individuals, a positive correlation between the logarithm of the locus-specific

-4.5

Log Mutation rate

-4

-3.5

-3

-2.5

-2

-1.5

-1 5.00

10.00

15.00

20.00

25.00

30.00

35.00

Geometric mean of LRPR Fig. 3. Correlation between the logarithm of mutation rate and geometric mean of LRPR size.

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mutation rate and He at 33 STR loci was evaluated with Spearman’s test (Fig. 2 and Table S5, linear correlation coefficient r = 0.69, p < 0.05), which was similar to the data derived from Lu et al. for 24 loci [14] but inconsistent with Leopoldino and Pena’s conclusions for nine loci [15], partially due to the limited sample and/or locus size. LRPR, also known as the longest uninterrupted repeats in the variable stretch, was correlated with the mutation rates expressed as an exponential function in previous reports [4,14,15] and this study (Fig. 3 and Table S6, curvilinear correlation coefficient r = 0.646, p < 0.05). Some of the loci, such as D7S3048 (21.86, 3.05), D13S325 (20.51, 3.05) and D20S161 (17.26, 3.42) fitted poorly with the positive tendency, possibly due to the relatively limited sample size compared with others. Locus D21S11 (31.02, 2.44) reversed the positive tendency and indicated a medium mutation rate with the highest geometric mean of LRPR. The mutation rates were correlated with short, medium, and long allele sizes, respectively, based on an altered category described by Ge et al. [26]. Data in Table S7 indicate a significant difference in mutation expansion or contraction counts in both short and long allele sizes (p < 0.01), i.e., mutations with repeat expansions occurred more frequently in short alleles, while repeat contractions were more common in long alleles. Similar findings were noticed in other reports [14,26]. No significant difference between mutation expansion and contraction counts was found in the medium-sized allele group (p > 0.05). In this study, a credible forensic dataset for locus-specific mutation rates of 33 loci has been established in a high number of parents/child-trio cases from Southwest Chinese Hans: The overall mutation rate across 33 loci from 10,636 parent-child trio cases in this study was consistent with other reports. Some of the mutations was reported for the first time. Most of the locusspecific mutation rates varied between populations from different ethnicities and geographical regions. A vast majority of mutations were single-step repeats involving gain/loss with no significant difference between their counts. Mutations occurred more frequently in males than in females. The correlations between He, geometric mean of LRPR, allele sizes and locus-specific mutation rates were investigated respectively. This study is in accordance with the guidelines suggested for publication of population genetic data by the journal and the International Society for Forensic Genetics (ISFG) recommendations [27]. Conflict of interest None. Acknowledgments This study was supported by grants from the National Natural Science Foundation of China (Nos. 81471827, 81202387), Applied Basic Research Programs of Science and Technology Commission Foundation of Sichuan Province (No. 2013JY0013), Outstanding Youth Fund of Sichuan University (No. 2014SCU04A14) and General Research Project of Education Department Foundation of Sichuan Province (No. 12SB224). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. fsigen.2016.03.009.

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