FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2154782029> ?p ?o ?g. }

• W2154782029 endingPage "1415" @default.
• W2154782029 startingPage "1408" @default.
• W2154782029 abstract "SummaryIn 10,844 parent/child allelic transfers at nine short-tandem-repeat (STR) loci, 23 isolated STR mismatches were observed. The parenthood in each of these cases was highly validated (probability >99.97%). The event was always repeat related, owing to either a single-step mutation (n=22) or a double-step mutation (n=1). The mutation rate was between 0 and 7×10−3 per locus per gamete per generation. No mutations were observed in three of the nine loci. Mutation events in the male germ line were five to six times more frequent than in the female germ line. A positive exponential correlation between the geometric mean of the number of uninterrupted repeats and the mutation rate was observed. Our data demonstrate that mutation rates of different loci can differ by several orders of magnitude and that different alleles at one locus exhibit different mutation rates. In 10,844 parent/child allelic transfers at nine short-tandem-repeat (STR) loci, 23 isolated STR mismatches were observed. The parenthood in each of these cases was highly validated (probability >99.97%). The event was always repeat related, owing to either a single-step mutation (n=22) or a double-step mutation (n=1). The mutation rate was between 0 and 7×10−3 per locus per gamete per generation. No mutations were observed in three of the nine loci. Mutation events in the male germ line were five to six times more frequent than in the female germ line. A positive exponential correlation between the geometric mean of the number of uninterrupted repeats and the mutation rate was observed. Our data demonstrate that mutation rates of different loci can differ by several orders of magnitude and that different alleles at one locus exhibit different mutation rates. Short tandem-repeat (STR) polymorphisms (Edwards et al., 1991aEdwards AI Civitello A Hammond HA Caskey CT DNA typing and genetic mapping with trimeric and tetrameric tandem repeats.Am J Hum Genet. 1991; 49: 746-756PubMed Google Scholar; Tautz and Schlotterer, 1994Tautz D Schlotterer C Simple sequences.Curr Opin Genet Dev. 1994; 4: 832-837Crossref PubMed Scopus (248) Google Scholar) have become a powerful tool for human identification (Gill et al., 1994Gill P Ivanov PL Kimpton C Piercy R Benson N Tully G Evett I et al.Identification of the remains of the Romanov family by DNA analysis.Nat Genet. 1994; 6: 130-135Crossref PubMed Scopus (470) Google Scholar), chromosome mapping and linkage analysis (Hearne et al., 1992Hearne CM Ghosh S Todd JA Microsatellites for linkage analysis of genetic traits.Trends Genet. 1992; 8: 288-294Abstract Full Text PDF PubMed Scopus (363) Google Scholar), and the study of molecular evolution (Meyer et al., 1995bMeyer E Wiegand P Rand SP Kuhlmann D Brack M Brinkmann B Microsatellite polymorphisms reveal phylogenetic relationships in primates.J Mol Evol. 1995; 41: 10-14Crossref PubMed Scopus (46) Google Scholar) and population genetics (Bowcock et al., 1994Bowcock AM Ruiz-Linares A Tomfohrde J Minch E Kidd JR Cavalli-Sforza LL High resolution of human evolutionary trees with polymorphic microsatellites.Nature. 1994; 368: 455-457Crossref PubMed Scopus (1502) Google Scholar; Brinkmann et al. Brinkmann et al., 1996aBrinkmann B Meyer E Junge A Complex mutational events at the HumD21S11 locus.Hum Genet. 1996; 98: 60-64Crossref PubMed Scopus (46) Google Scholar,Brinkmann et al., 1996bBrinkmann B Sajantila A Goedde HW Matsumoto H Nishi K Wiegand P Population genetic comparisons among eight populations using allele frequency and sequence data from three microsatellite loci.Eur J Hum Genet. 1996; 4: 175-182PubMed Google Scholar). Microsatellite instability and/or generation of new alleles can be disease related (Richards and Sutherland, 1996Richards RI Sutherland GR Repeat offenders: simple repeat sequences and complex genetic problems.Hum Mutat. 1996; 8: 1-7Crossref PubMed Scopus (18) Google Scholar). With regard to microsatellites, several studies exist dealing with mutation events in eukaryotes (Petes et al., 1997Petes TD Greenwell PW Dominska M Stabilization of microsatellite sequences by variant repeats in the yeast Saccharomyces cerevisiae.Genetics. 1997; 146: 491-498PubMed Google Scholar; Wierdl et al., 1997Wierdl M Dominska M Petes TD Microsatellite instability in yeast: dependence on the length of the microsatellite.Genetics. 1997; 146: 769-779Crossref PubMed Google Scholar), but there are limited data concerning human genetics (Jin et al., 1996Jin L Macaubas C Hallmayer J Kimura A Mignot E Mutation rate varies among alleles at a microsatellite locus: phylogenetic evidence.Proc Natl Acad Sci USA. 1996; 93: 15285-15288Crossref PubMed Scopus (140) Google Scholar). Weber and Wong, 1993Weber JL Wong C Mutation of human short tandem repeats.Hum Mol Genet. 1993; 2: 1123-1128Crossref PubMed Scopus (1298) Google Scholar have typed mutation events in cell lines from CEPH families and have validated ∼20 such events in di-, tri-, and tetranucleotide loci with an average mutation rate of 1.2×10−3. Heyer et al., 1997Heyer E Puymirat J Dieltjes P Bakker E De Knijff P Estimating Y chromosome specific microsatellite mutation frequencies using deep rooting pedigrees.Hum Mol Genet. 1997; 6: 799-803Crossref PubMed Scopus (224) Google Scholar estimated Y-chromosome STR mutation rates from the analysis of pedigrees spanning several generations. They found a mean mutation rate of 0.2%, which is close to the rate found by Weber and Wong, 1993Weber JL Wong C Mutation of human short tandem repeats.Hum Mol Genet. 1993; 2: 1123-1128Crossref PubMed Scopus (1298) Google Scholar. Others have performed computer simulations under several assumptions, compared these simulations to actual data, and formed conclusions regarding mutation rates and mechanisms (Valdes et al., 1993Valdes AM Slatkin M Freimer NB Allele frequencies at microsatellite loci: the stepwise mutation model revisited.Genetics. 1993; 133: 737-749PubMed Google Scholar; DiRienzo et al., 1994DiRienzo A Peterson AC Garza JC Valdes AM Slatkin M Freimer NB Mutational processes of simple-sequence repeat loci in human populations.Proc Natl Acad Sci USA. 1994; 91: 3166-3170Crossref PubMed Scopus (1215) Google Scholar). Several other species also have been investigated (Glenn et al., 1996Glenn TC Stephan W Dessauer HC Braun MJ Allelic diversity in alligator microsatellite loci is negatively correlated with the GC content of flanking sequences and evolutionary conservation of the PCR amplifiability.Mol Biol Evol. 1996; 13: 1151-1154Crossref PubMed Scopus (59) Google Scholar). From the analysis of such data, it is obvious that single (repeat)–step mutations account for ∼90% of STR mutation events, followed by double-step mutations and a very limited number of multistep mutations. The induction of mutations in minisatellites, by radiation, has been studied in the Hiroshima and Nagasaki areas (Kodaira et al., 1995Kodaira M Satoh C Hiyama K Toyama K Lack of effects of atomic bomb radiation on genetic instability of tandem-repetitive elements in human germ cells.Am J Hum Genet. 1995; 57: 1275-1283PubMed Google Scholar) and in the Chernobyl area (Dubrova et al., 1996Dubrova YE Nesterov VN Krouchinsky NG Ostapenko VA Neumann R Neil DL Jeffreys AJ Human minisatellite mutation rate after the Chernobyl accident.Nature. 1996; 380: 683-686Crossref PubMed Scopus (333) Google Scholar). Whereas the former study found no evidence for an increase in the mutation rate, the latter study detected a twofold increase. In this study, we have investigated in depth ∼11,000 meioses in one pentameric and eight tetrameric loci. Approximately 16 informative systems including four or five STRs were applied in routine paternity testing. In cases of isolated STR mismatches between parent(s) and child, further in-depth analysis was performed. The first step was to include another five STRs. If the mismatch remained isolated, statistical analysis of the probability of the respective parenthood was performed. Since the discrepant system was always included in the calculation (Fimmers et al., 1992Fimmers R Henke L Henke J Baur M How to deal with mutations in DNA testing.in: Rittner C Schneider PM Advances in forensic haemogenetics 4. Springer Verlag, Berlin, Heidelberg1992: 285-287Crossref Google Scholar), the overall parenthood probability decreased significantly after this step, by two or more orders of magnitude. The assumption of a new mutation was made only if the final figure—that is, after inclusion of four or five additional STRs—attained or exceeded 99.97%. For cases of confirmed new mutations, all alleles in the father, mother, and child, at the locus involved, were sequenced. In accordance with the literature (e.g., Weber and Wong, 1993Weber JL Wong C Mutation of human short tandem repeats.Hum Mol Genet. 1993; 2: 1123-1128Crossref PubMed Scopus (1298) Google Scholar) we have defined the origin of the “new” allele as follows: If there were two possibilities, the shortest mutational step was considered to be the actual one. For example, if one parental allele differed by one repeat and the other by two repeats, when compared with that of the child, we inferred a one-step mutation. Also, if for structural reasons one alternative was far more likely than the other, this step was considered to be the actual one (fig. 1). If two parental alleles exhibited the same difference when compared with the new one, the origin was declared unknown. If exclusion was possible for both parents, then the origin was declared uncertain. For further details, see figure 1. DNA was extracted from venous-blood samples and quantified (Miller et al., 1988Miller SA Dykes DD Pollsky HF A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17178) Google Scholar; Waye et al., 1989Waye JS Presley LA Budowle B Shutler GS Fourney RM A simple and sensitive method for quantifying human genomic DNA in forensic specimen extracts.Biotechniques. 1989; 7: 852-855Crossref PubMed Scopus (6) Google Scholar). PCR reactions were performed in accordance with the following literature: for HumTH01 (GenBank accession number D00269), Edwards et al., 1991aEdwards AI Civitello A Hammond HA Caskey CT DNA typing and genetic mapping with trimeric and tetrameric tandem repeats.Am J Hum Genet. 1991; 49: 746-756PubMed Google Scholar, as modified by Wiegand et al., 1993Wiegand P Budowle B Rand S Brinkmann B Forensic validation of the STR systems SE33 and TC11.Int J Legal Med. 1993; 105: 315-320Crossref PubMed Scopus (159) Google Scholar; for HumVWA (GenBank accession number M25716), Kimpton et al., 1992Kimpton C Walton A Gill P A further tetranucleotide repeat polymorphism in the vWF gene.Hum Mol Genet. 1992; 1: 287Crossref PubMed Scopus (247) Google Scholar, as modified by Möller et al., 1994Möller A Meyer E Brinkmann B Different types of structural variation in STRs: HumFES/FPS, HumVWA and HumD21S11.Int J Legal Med. 1994; 106: 319-323Crossref PubMed Scopus (122) Google Scholar; for HumF13B (GenBank accession number M64554), Nishimura and Murray, 1992Nishimura DY Murray JC A tetranucleotide repeat for the F13B locus.Nucleic Acids Res. 1992; 20: 1167Google Scholar, as modified by Alper et al., 1995Alper B Meyer E Schürenkamp M Brinkmann B HumFES/FPS and HumF13B: Turkish and German population data.Int J Legal Med. 1995; 108: 93-95Crossref PubMed Scopus (31) Google Scholar; for HumD21S11 (GenBank accession number M84567), Sharma and Litt, 1992Sharma V Litt M Tetranucleotide repeat polymorphism at the D21S11 locus.Hum Mol Genet. 1992; 1: 67Crossref PubMed Scopus (117) Google Scholar, as modified by Möller et al., 1994Möller A Meyer E Brinkmann B Different types of structural variation in STRs: HumFES/FPS, HumVWA and HumD21S11.Int J Legal Med. 1994; 106: 319-323Crossref PubMed Scopus (122) Google Scholar; for HumCD4 (GenBank accession number M86525), Edwards et al., 1991bEdwards MC Clemens PR Tristan M Pizzuti A Gibb RA Pentanucleotide repeat length polymorphism at the human CD4 locus.Nucleic Acids Res. 1991; 19: 4791Crossref PubMed Scopus (80) Google Scholar; for HumACTBP2 (GenBank accession number V00481), Polymeropoulos et al., 1992Polymeropoulos MH Rath DS Xiao H Merril CR Tetranucleotide repeat polymorphism at the human beta-actin related pseudogene H-beta-Ac-psi-2 (ACTBP2).Nucleic Acids Res. 1992; 20: 1432Crossref PubMed Scopus (144) Google Scholar, as modified by Möller and Brinkmann, 1994Möller A Brinkmann B Locus ACTBP2 (SE33): sequencing data reveal considerable polymorphism.Int J Legal Med. 1994; 106: 262-267Crossref PubMed Scopus (86) Google Scholar; for HumD12S391 (GenBank accession number G08921), Lareu et al., 1996Lareu MV Pestoni C Schürenkamp M Rand S Brinkmann B Carracedo A A highly variable STR at the D12S391.Int J Legal Med. 1996; 109: 134-138Crossref PubMed Scopus (76) Google Scholar; for HumFGA (GenBank accession number G33478), Barber et al., 1996Barber MD McKeown BJ Parkin B Structural variation in the alleles of a short tandem repeat system at the human alpha fibrinogen locus.Int J Legal Med. 1996; 108: 180-185Crossref PubMed Scopus (53) Google Scholar, as modified by Rolf et al., 1997aRolf B Möller K Schürenkamp M Brinkmann B Automatische Analyse von hoch effizienten STRs.Rechtsmedizin. 1997; 7: 157-161Crossref Scopus (9) Google Scholar; and, for HumFES (GenBank accession number M14589), Polymeropoulos et al., 1991Polymeropoulos MH Rath DS Xiao H Merril CR Tetranucleotide repeat polymorphism at the human c-fes/fps proto-oncogene (FES).Nucleic Acids Res. 1991; 19: 4018Google Scholar and Möller et al., 1994Möller A Meyer E Brinkmann B Different types of structural variation in STRs: HumFES/FPS, HumVWA and HumD21S11.Int J Legal Med. 1994; 106: 319-323Crossref PubMed Scopus (122) Google Scholar. Separation of alleles was achieved under either native gel conditions (Allen et al., 1989Allen RC Graves G Budowle B Polymerase chain reaction amplification products separated on rehydratable polyacrylamide gels and stained with silver.Biotechniques. 1989; 7: 736-744Crossref PubMed Google Scholar) or denaturing conditions (ACTBP2, D21S11, D12S391, and FGA), by application of fluorescence detection (AlfExpress, Pharmacia). Alleles were always identified by direct comparisons with sequenced allelic ladders, either visually (side by side) or by use of a computer. The measured length always exactly corresponded to the sequenced length, the precision being better than ±0.5 bp (variation width). Thus, length differences, between alleles, of 1 bp were routinely resolved, and even point mutations were detected, if native conditions were applied (Möller et al., 1994Möller A Meyer E Brinkmann B Different types of structural variation in STRs: HumFES/FPS, HumVWA and HumD21S11.Int J Legal Med. 1994; 106: 319-323Crossref PubMed Scopus (122) Google Scholar). All amplified alleles of the relevant system were excised from silver-stained gels, were extracted, and subsequently were reamplified (Möller and Brinkmann, 1994Möller A Brinkmann B Locus ACTBP2 (SE33): sequencing data reveal considerable polymorphism.Int J Legal Med. 1994; 106: 262-267Crossref PubMed Scopus (86) Google Scholar). Sequencing was performed by use of Taq Cycle sequencing with commercially available kits and equipment (ABI 373 Sequencer and ABI sequencing Kit, Applied Biosystems). Both strands were sequenced for confirmation, with the exception of ACTBP2, for which one strand was sequenced twice. Among 10,844 parent/child allele transfers at nine loci, we observed 23 mutations at six of the loci (table 1 and fig. 1). The pedigrees and the alleles present in the parents and the child are shown in figure 1. Approximately 98% of the paternity cases were Caucasoids living in Germany or Austria; all father-mother-child triplets showing mutations were from this major ethnic group. In figure 2, the allele frequencies and the sequence of the alleles present in the general Caucasoid population are shown. The allele frequencies are updates of previously published data sets (Meyer et al., 1995aMeyer E Wiegand P Brinkmann B Phenotype differences of STRs in 7 human populations.Int J Legal Med. 1995; 107: 314-322Crossref PubMed Scopus (43) Google Scholar; Rolf et al., 1997aRolf B Möller K Schürenkamp M Brinkmann B Automatische Analyse von hoch effizienten STRs.Rechtsmedizin. 1997; 7: 157-161Crossref Scopus (9) Google Scholar; Brinkmann et al., 1998Brinkmann B Junge A Meyer E Wiegand P Population genetic diversity in relation to microsatellite heterogeneity.Hum Mutat. 1998; 11: 135-144Crossref PubMed Scopus (57) Google Scholar). In addition to the length variation due to the number of repeats, sequence differences due to point mutations and insertions/deletions that interrupt the homogeneous repeat stretch are quite common at microsatellite loci (fig. 2). Sequence differences between the alleles at one locus are indicated by the shading of the bars in the figures showing frequency versus size (fig. 2). All mutations observed were either repeat losses or repeat gains. Twenty-two were single-step mutations, and one was a double-step mutation (figs. 1 and 2 [indicated by arrows]). None of the mutations observed was an insertion or deletion of an incomplete repeat. If all the repeat gains and losses are summarized, the result is the loss of two repeats; that is, in ∼11,000 transfers, a small DNA loss occurred.Table 1Number of Meioses and Mutations, Compared with the Mutation Rate and the Heterozygosity Rate of the Nine STR LociLocusMean LengthaThe geometric mean of the number of uninterrupted repeats in the variable stretch.No. of MeiosesbTotal paternal and maternal allelic transfers.No. of MutationsMutation Rate (%)Heterozygosity RatecWith regard to the German population sample in this study.CD45.669690.0.67F13B8.741,0330.0.67TH017.782,0080.0.78FES10.798501.117.65VWA10.82,0134.199.81D12S39111.475621.178.87D21S1111.05571.18.86FGA13.841,2465.401.86ACTBP215.211,60811.684.93a The geometric mean of the number of uninterrupted repeats in the variable stretch.b Total paternal and maternal allelic transfers.c With regard to the German population sample in this study. Open table in a new tab The mutation rate showed a positive correlation to the geometric mean of the number of variable uninterrupted repeats. The latter relation can be expressed as an exponential function (fig. 3). In several cases, the mother or the “father” was missing from the triplet, but the overall ratio of maternal to paternal meioses was ∼1, for all loci examined, with only a minor deviation (∼±1%). However, the ratio of paternal versus maternal mutations was 17:3, whereas for three additional cases the origin remained unclear. At three loci, we observed 20 of the mutations (table 1 and figs. 1 and 3). The major mutational activity at these three loci was shifted slightly to the longer alleles in the unimodal distribution. It is now generally accepted that replication slippage (Levinson and Gutman, 1987Levinson G Gutman GA Slipped strand mispriming: a major mechanism for DNA sequence evolution.Mol Biol Evol. 1987; 4: 203-221PubMed Google Scholar) is the major mechanism causing new mutations in microsatellites. In our 23 observations, no indication of other possible mechanisms was found. Also, in accordance with the literature, there seemed to exist a strong correlation with the number of homogeneous repeats (Wierdl et al., 1997Wierdl M Dominska M Petes TD Microsatellite instability in yeast: dependence on the length of the microsatellite.Genetics. 1997; 146: 769-779Crossref PubMed Google Scholar). It has been concluded from studies of yeast that interspersed irregular repeats have an inhibitory effect on mutation events (Petes et al., 1997Petes TD Greenwell PW Dominska M Stabilization of microsatellite sequences by variant repeats in the yeast Saccharomyces cerevisiae.Genetics. 1997; 146: 491-498PubMed Google Scholar). This was confirmed in our study. The fact that the majority of the mutation events in our study were shifted to the longer alleles in the (unimodal) distribution profile(s) in the population examined supports the finding of the higher susceptibility of long (homogeneous) stretches to mutation events. In a subgroup of three systems (fig. 2), we observed no mutations. In these systems, the allele lengths versus frequency distributions were not unimodal, and the geometric means of the number of homogeneous repeats were ≤9. In all the other systems, we observed mutations. Their repetitive regions were longer, the geometric means of the number of repeats of homogeneous stretches being >10. In addition, their allele lengths versus frequency distributions were approximately unimodal. In some cases, bimodal distributions of alleles are caused by two subgroups of alleles with differences in the sequence and arrangement of repeats. For example, this was the case at the loci D21S11 and ACTBP2. On the basis of the aforementioned relationships, a number of population-genetics findings are readily interpreted: The multimodal distributions (fig. 2) of the systems with low mutation rates can be explained by genetic drift and founder effects. Homogeneous repeat regions with repeat numbers <10 seem to mutate extremely seldom. Therefore, these systems can be used for ethnic-affiliation estimations (Meyer et al., 1995aMeyer E Wiegand P Brinkmann B Phenotype differences of STRs in 7 human populations.Int J Legal Med. 1995; 107: 314-322Crossref PubMed Scopus (43) Google Scholar; Shriver et al., 1997Shriver MD Smith MW Jin L Marcini A Akey JM Deka R Ferrell RE Ethnic-affiliation estimation by use of population-specific DNA markers.Am J Hum Genet. 1997; 60: 957-964PubMed Google Scholar), since differences in allele frequencies between populations are not obscured by new mutations. Interrupted alleles (i.e., alleles with interspersed irregular units) mutate less often than uninterrupted alleles: the best example is ACTBP2, for which we observed eight mutations (rate 1.2%) in the uninterrupted alleles (40% of all alleles; depicted by the left peak in fig. 2). The geometric mean of the lengths of these alleles is 18 repeats. In contrast, only three mutations (rate 0.3%) were observed in the interrupted alleles (60% of all alleles; depicted by the right peak in fig. 2). The geometric mean of the lengths of these alleles is 28 repeats. Although the interrupted alleles are longer, they are less susceptible to mutation, evidently because their homogeneous repeat stretches have a mean length of only 14 repeats, owing to the interspersed repeats. For the same reason, VWA allele 14, which has only 3 regular repeats on either side of a variant repeat (fig. 2), hardly ever mutates. So far, no “daughter allele” of VWA allele 14 (e.g., VWA allele 13* or 15*) has been observed, even though a mutated allele 14* would migrate strikingly differently under native electrophoretic conditions and even though thousands of alleles 13 and 15 have been investigated, so far, and large numbers also have been sequenced. Similarly, no regular allele 14 has been observed; thus, repeat losses nearly never occur at allele 15, although the mutation rates of alleles 16 and 17 are rather high. Interestingly, Africans have a third group of alleles (Evett et al., 1997Evett IW Gill PD Lambert JA Oldroyd N Frazier R Watson S Panchal S et al.Statistical analysis of data for three British ethnic groups from a new STR multiplex.Int J Legal Med. 1997; 110: 5-9Crossref PubMed Scopus (52) Google Scholar) with consensus structures, but with lengths <14, that are separated from the longer alleles by allele 14*. These alleles might have been lost by bottleneck effects in Europeans/Asians and have not been reconstructed by mutations. Again, this indicates that the short fragments in this STR are nearly free of mutations. Similarly, daughter alleles of TH01 9.3—namely, 6.3, 7.3, 8.3, 10.3, etc.—have been detected only sporadically (Evett et al., 1997Evett IW Gill PD Lambert JA Oldroyd N Frazier R Watson S Panchal S et al.Statistical analysis of data for three British ethnic groups from a new STR multiplex.Int J Legal Med. 1997; 110: 5-9Crossref PubMed Scopus (52) Google Scholar; Klintschar et al., 1998Klintschar M Kozma Z Al Hammadi N Abdull Fatah M Nöhammer C A study on the short tandem repeat systems HumCD4, HumTH01 and HumFIBRA in a population sample from Yemen and Egypt.Int J Legal Med. 1998; 111: 107-109Crossref PubMed Scopus (18) Google Scholar). The same considerations apply to allele CD4 10 in Caucasoids. On the other hand, irregular units in the flanking region of the proper repeat region or close to it (e.g., FGA and D21S11 alleles denoted by the suffix “.2”) do not appear to have a strong inhibitory effect on mutations, as can be derived from the distribution profiles for which significant numbers of daughter alleles were observable. Three loci in our survey (FGA, VWA, and ACTBP2) have multiple repeat-like structures, in both flanking regions, that do not exhibit length variability (Möller et al., 1994Möller A Meyer E Brinkmann B Different types of structural variation in STRs: HumFES/FPS, HumVWA and HumD21S11.Int J Legal Med. 1994; 106: 319-323Crossref PubMed Scopus (122) Google Scholar; Barber et al., 1996Barber MD McKeown BJ Parkin B Structural variation in the alleles of a short tandem repeat system at the human alpha fibrinogen locus.Int J Legal Med. 1996; 108: 180-185Crossref PubMed Scopus (53) Google Scholar; Rolf et al., 1997bRolf B Schürenkamp M Junge A Brinkmann B Sequence polymorphism at the tetranucleotide repeat of the human beta-actin related pseudogene H-beta-Ac-psi-2 locus.Int J Legal Med. 1997; 110: 69-72Crossref PubMed Scopus (46) Google Scholar). The loci D12S391 and D21S11 have two and three regions, respectively, that express length variability. Interestingly, in our study, these five loci had the highest mutation rates and the longest homogeneous (uninterrupted) repeat regions. Thus, a question arises: does the repetition surrounding the so-called compound structure of the repeat region influence the mutation rate as well? Within one system, the mutation rate strongly correlates to the number of repeats, since longer alleles mutate more often. Thus, it is possible that compound structures are only an accompanying or side phenomenon without any triggering function for new mutations. However, we cannot rule out completely the possibility that these compound structures can (over long evolutionary periods) trigger, for example, the growth of homogeneous stretches, to an extent that makes them more susceptible to repeat slippage. We observed a small overall DNA loss in our study, although this observation may have been due to the limited sample size. The major mutation activity was found in the longer alleles and could have led to some distortion of the pure Gaussian shape of the allele length versus frequency distribution, with flatter foothills mainly on the right-hand side(s), if these alleles mutate in both directions with the same probability. This would coincide with the observation that the average number of repeats present in various primate species is lower than that present in humans and correlates negatively with their divergence time from humans (Meyer et al., 1995bMeyer E Wiegand P Rand SP Kuhlmann D Brack M Brinkmann B Microsatellite polymorphisms reveal phylogenetic relationships in primates.J Mol Evol. 1995; 41: 10-14Crossref PubMed Scopus (46) Google Scholar). However, the conservation of a Gaussian shape for the distribution for humans would require an excess of gains over losses on the left-hand side of the profile and an excess of losses over gains on the right-hand side. Interestingly, of the 13 mutations with known direction, on the right-hand side of the profile, 8 are repeat losses, and only 5 are repeat gains. Our observation seems to apply mainly to autosomal tetrameric (and one pentameric) microsatellites with high AT and AG proportions. We suggest that such events in Y-chromosome STRs should be evaluated more thoroughly before analogies can be established. There obviously exists a sex difference for mutations, at a ratio of ∼17:3 between males and females. In addition, the father's age seems to influence the mutation rate: the mean age (±SD) of all the fathers in our data set was 28.7±7.6 years, whereas the mean age of the fathers who were involved in the mutation events was 32.5±7.8 years. This difference is significant, with P=.01 in a t-test. The difference is associated with different numbers and types of cell divisions in germ-cell genesis; oogonia undergo ∼22 divisions before meiosis starts and oocytes are generated. Spermatogonia renew continuously by mitosis, and some continue through meioses, before they become sperm cells; thus, the sperm cells of older men have undergone more divisions than the cells of younger men. For a 29-year-old man, one can assume ∼350 divisions (Vogel and Motulsky, 1997Vogel F Motulsky AG Human genetics: problems and applications. 3d ed. Springer Verlag, Berlin, Heidelberg, New York1997Crossref Google Scholar). Therefore, the DNA in a “typical” sperm cell from a father in our study was replicated ∼16 times more often than the DNA in an oocyte. Consequently, the mutation rate, expressed per mitosis, seems to be somewhat lower in males. However, owing to the small number of mutation events observed in the females in our study, this difference is not very significant. Taken together, most of the variation at microsatellite loci can be assumed to be caused by males. This is in accordance with observations of other species in which higher rates for males also have been described (Shimmin et al., 1993Shimmin LC Chang BHJ Li WH Male driven evolution of DNA sequences.Nature. 1993; 362: 745-747Crossref PubMed Scopus (192) Google Scholar). Interestingly, in a recent study, Ellegran and Fridolfsson, 1997Ellegran H Fridolfsson AK Male driven evolution of DNA sequences in birds.Nature Genet. 1997; 17: 182-184Crossref PubMed Scopus (180) Google Scholar were able to demonstrate that very similar sex relationships also have been found in birds, although the females are heterogametic and the males are homogametic, for the W and Z sex chromosomes, respectively. Weber and Wong, 1993Weber JL Wong C Mutation of human short tandem repeats.Hum Mol Genet. 1993; 2: 1123-1128Crossref PubMed Scopus (1298) Google Scholar also found a very similar relationship (∼5:1 to 6:1) during their study of CEPH reference families. This work was supported partially by grant 6523/1 from the Jubilee Fund of the Austrian National Bank (to M.K.)." @default.
• W2154782029 created "2016-06-24" @default.
• W2154782029 creator A5009296138 @default.
• W2154782029 creator A5031227560 @default.
• W2154782029 creator A5040766812 @default.
• W2154782029 creator A5088094676 @default.
• W2154782029 creator A5091877491 @default.
• W2154782029 date "1998-06-01" @default.
• W2154782029 modified "2023-10-17" @default.
• W2154782029 title "Mutation Rate in Human Microsatellites: Influence of the Structure and Length of the Tandem Repeat" @default.
• W2154782029 cites W1504881874 @default.
• W2154782029 cites W1541290060 @default.
• W2154782029 cites W1592777209 @default.
• W2154782029 cites W160893397 @default.
• W2154782029 cites W180749791 @default.
• W2154782029 cites W1935763178 @default.
• W2154782029 cites W1945353891 @default.
• W2154782029 cites W1954171659 @default.
• W2154782029 cites W1978032139 @default.
• W2154782029 cites W1978781593 @default.
• W2154782029 cites W1980838072 @default.
• W2154782029 cites W1980913212 @default.
• W2154782029 cites W1981096658 @default.
• W2154782029 cites W2007057885 @default.
• W2154782029 cites W2011777535 @default.
• W2154782029 cites W2019249381 @default.
• W2154782029 cites W2032818552 @default.
• W2154782029 cites W2048025342 @default.
• W2154782029 cites W2048274970 @default.
• W2154782029 cites W2048949614 @default.
• W2154782029 cites W2049205303 @default.
• W2154782029 cites W2052809204 @default.
• W2154782029 cites W2060237458 @default.
• W2154782029 cites W2066797267 @default.
• W2154782029 cites W2068500379 @default.
• W2154782029 cites W2070473292 @default.
• W2154782029 cites W2071685834 @default.
• W2154782029 cites W2074015251 @default.
• W2154782029 cites W2075688126 @default.
• W2154782029 cites W2077547820 @default.
• W2154782029 cites W2085316620 @default.
• W2154782029 cites W2086057335 @default.
• W2154782029 cites W2086137665 @default.
• W2154782029 cites W2090223604 @default.
• W2154782029 cites W2090757997 @default.
• W2154782029 cites W2112066577 @default.
• W2154782029 cites W2117720768 @default.
• W2154782029 cites W2118094114 @default.
• W2154782029 cites W2131681278 @default.
• W2154782029 cites W2142659575 @default.
• W2154782029 cites W2160982584 @default.
• W2154782029 cites W2164109844 @default.
• W2154782029 cites W2321278409 @default.
• W2154782029 cites W2408997352 @default.
• W2154782029 cites W4253451516 @default.
• W2154782029 doi "https://doi.org/10.1086/301869" @default.
• W2154782029 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1377148" @default.
• W2154782029 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/9585597" @default.
• W2154782029 hasPublicationYear "1998" @default.
• W2154782029 type Work @default.
• W2154782029 sameAs 2154782029 @default.
• W2154782029 citedByCount "705" @default.
• W2154782029 countsByYear W21547820292012 @default.
• W2154782029 countsByYear W21547820292013 @default.
• W2154782029 countsByYear W21547820292014 @default.
• W2154782029 countsByYear W21547820292015 @default.
• W2154782029 countsByYear W21547820292016 @default.
• W2154782029 countsByYear W21547820292017 @default.
• W2154782029 countsByYear W21547820292018 @default.
• W2154782029 countsByYear W21547820292019 @default.
• W2154782029 countsByYear W21547820292020 @default.
• W2154782029 countsByYear W21547820292021 @default.
• W2154782029 countsByYear W21547820292022 @default.
• W2154782029 countsByYear W21547820292023 @default.
• W2154782029 crossrefType "journal-article" @default.
• W2154782029 hasAuthorship W2154782029A5009296138 @default.
• W2154782029 hasAuthorship W2154782029A5031227560 @default.
• W2154782029 hasAuthorship W2154782029A5040766812 @default.
• W2154782029 hasAuthorship W2154782029A5088094676 @default.
• W2154782029 hasAuthorship W2154782029A5091877491 @default.
• W2154782029 hasBestOaLocation W21547820291 @default.
• W2154782029 hasConcept C104317684 @default.
• W2154782029 hasConcept C141231307 @default.
• W2154782029 hasConcept C159985019 @default.
• W2154782029 hasConcept C180754005 @default.
• W2154782029 hasConcept C192562407 @default.
• W2154782029 hasConcept C27149982 @default.
• W2154782029 hasConcept C2777814067 @default.
• W2154782029 hasConcept C501734568 @default.
• W2154782029 hasConcept C54355233 @default.
• W2154782029 hasConcept C61320498 @default.
• W2154782029 hasConcept C70721500 @default.
• W2154782029 hasConcept C86803240 @default.
• W2154782029 hasConcept C98638677 @default.
• W2154782029 hasConceptScore W2154782029C104317684 @default.
• W2154782029 hasConceptScore W2154782029C141231307 @default.
• W2154782029 hasConceptScore W2154782029C159985019 @default.
• W2154782029 hasConceptScore W2154782029C180754005 @default.

• next