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The X Chromosome Shows Less Genetic Variation at Restriction Sites Than the Autosomes

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The X Chromosome Shows Less Genetic Variation at Restriction Sites Than the Autosomes Am J Hum Genet 39:438-451, 1986 The X Chromosome Shows Less Genetic Variation at Restriction Sites Than the Autosomes M. H. HOFKER,l M. I. SKRAASTAD, A. A. B. BERGEN, M. C. WAPENAAR, E. BAKKER, A. MILLINGTON-WARD, G. J. B. VAN OMMEN, AND P. L. PEARSON SUMMARY Using a standard technique, 122 single-copy probes were screened for their ability to detect restriction fragment length polymorphisms (RFLPs) in the human genome. The use of a standardized RFLP screening enables the introduction of statistical methods in the analy- sis of differences in RFLP content between chromosomes and en- zymes. RFLPs were detected from panels containing at least 17 unre- lated chromosomes, digested with Taql, MspI, BgII, HindIll, EcoRI, and PstI. Forty autosomal probes, representing a sample of 2,710 base pairs (bp) per haploid genome, were tested, and 24 RFLPs were found. With 82 X-chromosomal probes, 17 RFLPs were found in 6,228 bp per haploid genome. The frequency of X-chromosomal RFLPs is three times less than that of the autosomes; this difference is highly significant (P = < .001). The frequency of RFLPs revealed by various restriction enzymes and the possibility that the X chromosome is a "low mutation" niche in the human genome are discussed. INTRODUCTION Restriction fragment length polymorphisms (RFLPs) have been recognized as a powerful tool in the construction of linkage maps [1] and for carrier detection and prenatal diagnosis of genetic diseases [2]. Their applicability compares favorably to other genetic markers, since they are highly abundant in the Received February 25, 1986; revised May 9, 1986. This work was supported by grant nr. 13-23-47 from the foundation for medical research FUNGO, which is subsidized by the Netherlands Organization for the Advancement of Pure Scientific Research (ZWO), and by grant nr. 28-878 from the Netherlands Prevention Fund. ' All authors: Department of Human Genetics, Sylvius Laboratories, State University of Leiden, 2333 AL, Leiden, The Netherlands. © 1986 by the American Society of Human Genetics. All rights reserved. 0002-9297/86/3904-0002$02.00 438 GENETIC VARIATION OF THE X CHROMOSOME 439 genome and DNA can be isolated from all nucleated cells. To date, more than 300 RFLPs have been identified and assigned to specific chromosomes [3]. For some chromosomes ( lp, 21, Xp, and distal Xq), a sufficient density of markers has been reached to permit general genetic disease mapping and use in genetic counseling [3]. Early investigations of the 0-globin region suggested 1:100 bp to be poly- morphic [4]. Although this figure has since been confirmed for the serum albu- min locus [5], several examples have been reported (a1-antitrypsin [6], thyro- globulin [7], factor VIII [8]) in which extremely low RFLP frequencies were found. This implies that the degree of polymorphism in the human genome can vary between different gene regions. However, in order to accurately quantify the average level of DNA variation in the human genome, a random series of probes for the detection of RFLPs should be used [9, 10]. In an initial study, Cooper et al. suggested that a lower RFLP content was present in the X chromosome than in the autosomes [10]. However, because of the small number of X probes employed, the statistical significance of their observations could not be verified. Initial data from our laboratory were consistent with this finding, indicating that X-chromosomal RFLPs occur with a frequency of 1: 1,000 bp per haploid genome [ 1], substan- tially lower than proposed for random autosomal probes [12, 13]. Here, we have extended these findings by the use of many more probes. To get unbiased data, the probes were tested on the same panel of 17-38 unrelated chromosomes restricted with the same set of enzymes. Heterozygosity was estimated in two ways. The first can be defined as the probability of finding a polymorphic base pair in all sites examined and takes into account the numbers of chromosomes investigated [9]. The second can be expressed as the chance that any base pair in a haploid genome is polymorphic, according to the method of Jeffreys [4], as modified by Ewens et al. [14], and is independent of the number of chromosomes investigated. The large series of probes employed in this study can also be used to test whether significant differences exist between enzymes in their ability to reveal RFLPs. The enzyme panel includes TaqI and MspI, both containing the CpG dimer, for which a higher variability has been reported [13]. MATERIALS AND METHODS X-Chromosome Specific Probes The X probes were isolated from libraries from flow-sorted chromosomes [15, 16] and characterized as described [11] or obtained from a cosmid library of a hamster hybrid cell line with a single human X chromosome. In the latter case, human inserts were identified initially by their human repeats. Each cosmid was digested with EcoRI and subcloned in pAT153. Recombinant plasmids were identified as human specific single- copy probes following hybridizing to filters containing human and hamster DNA. They were further characterized on a panel consisting of cell hybrids and human cell lines with unbalanced X-chromosomal abnormalities to prove their X-chromosome specific- ity. Furthermore, DNA of 100 X-specific cosmids was pooled together, digested with EcoRI and PstI or SauIIIA, and subcloned, allowing the rapid isolation of a large series of single-copy probes (Hofker et al., submitted for publication). 440 HOFKER ET AL. Autosomal Probes EcoRI-digested genomic DNA was size selected, and the 0.5-2.0-kilobase (kb) frac- tion was cloned in pAT153 and transformed into E. coli. Recombinant plasmids were isolated, labeled, and hybridized to genomic filters. Single-copy probes were identified and localized to specific chromosomes with a hybrid cell panel. A fraction enriched for chromosome 21 was obtained from a mouse hybrid cell line containing chromosome 21 as the only human chromosome by using a sedimentation chamber technique [17]. This DNA was partially cut with MboI and cloned in EMBL3. DNA of phages, containing human repeats, was digested with PstI and further sub- cloned into pAT153. The single-copy clones were identified, their chromosome 21 origin verified, and subregional localization obtained with cell hybrids and using human cell lines with unbalanced chromosome 21 aberrations. RFLP Investigations Single-copy probes were investigated for their ability to detect restriction site variabil- ity. A minimum of 17 chromosomes per probe per enzyme ensured a 95% chance of detecting RFLPs with a minor allele frequency greater than 10% [18]. The restriction enzymes TaqI, MspI, BglII, EcoRI, PstI, and HindIII were used throughout. To be certain that only well-characterized RFLPs are involved, potential polymorphic bands were related to a dosage change at the major allele from two to one copy in those individuals in which an RFLP was thought to occur. High-frequency RFLPs were also confirmed by their Mendelian inheritance pattern. Calculations For ease of calculation, the number of restriction sites examined has been assumed to be equal to the number of autoradiographic bands plus one. The assumption is that the bands reflect a contiguous stretch of DNA disregarding possible small internal frag- ments. This will lead to a systematic underestimation both of the number of tested sites and RFLPs detected, since some fragments will either be too small or too long to be mutually detected using standard Southern blotting methods. However, such errors are likely to affect the autosomal and the X-chromosomal data equally. The number of sites, multiplied by the number of base pairs present in the restriction site, gives the total number of base pairs screened per haploid genome (X). If n-chromosomes are tested then n x X is the total number of base pairs examined. Heterozygosity may be esti- mated in one of two ways: (1) Cooper and Schmidtke [9] suggest the use ofthe estimator of Nei [19], which in its form suitable for RFLP analysis gives: HN = 1 - {(alb)2 + [(b - a)Ib]2} , (1) where a is the total number of variants and b is the total number of base pairs tested (n x X). HN is the probability that two homologous DNA sequences will have different base pairs at a given site. (2) Ewens et al. [14] propose the following estimator: HE= v/2X, (2) where HE is the fraction of sites in the haploid genome at which two or more nucleotide types appear and v is the number of polymorphic sites observed. This formula takes no account of the allele frequencies involved. GENETIC VARIATION OF THE X CHROMOSOME 441 RESULTS Heterogeneity of the X chromosome In total, 82 X-specific single-copy probes were tested for their ability to detect RFLPs (table 1A-D and table 3). From the chromosome specific A charon 21a and A gtWES libraries, 23 unique sequence X probes were isolated. Four polymorphic sites were discovered in 1,922 nonhomologous bp per hap- loid genome. Over all chromosomes, 11 alleles were found in 38.4 kb. From 16 X-specific cosmid clones, 16 single-copy EcoRI fragments were isolated. Five polymorphic sites were found, resulting in 10 alleles. This represents 1,484 bp of the haploid genome; 25 kb was screened over all chromosomes tested. From the pooled X-specific cosmids, 37 single-copy X probes were isolated. These detected seven polymorphic sites in 2,636 bp, yielding 25 alleles in 45 kb over all chromosomes. From the total genomic plasmid library, three X probes were detected and one polymorphism was found. There appears to be no statistical evidence that any of the isolation strategies generated probes with different ability to detect RFLPs, and the data for all X.probes were pooled accordingly.
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