Proc. Nati. Acad. Sci. USA Vol. 89, pp. 4598-4602, May 1992 Medical Sciences Integration of gene maps: Chromosome 1 (human genome/inkae) A. COLLINS*, B. J. KEATSt, N. DRACOPOLIt, D. C. SHIELDS*, AND N. E. MORTON* *CRC Research Group in Genetic Epidemiology, Department of Child Health, University of Southampton, Southampton, S09 4XY, United Kingdom; tDepartment of Biometry and Genetics, Louisiana State University Center, 1901 Perdido Street, New Orleans, LA 70112; and tCenter for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street, Cambridge, MA 02139 Contributed by N. E. Morton, February 10, 1992 ABSTRACT A composite map of 177 locI has been con- standard lod tables extracted from the literature. Multiple structed in two steps. The first combined pairwise logarithm- pairwise analysis of these data was performed by the MAP90 of-odds scores on 127 loci Into a comprehensive genetic map. computer program (6), which can estimate an errorfrequency Then this map was projected onto the physical map through e (7) and a mapping parameter p such that map distance w is cytogenetic assignments, and the small amount ofphysical data a function of 0, e and p (8). It also includes a bootstrap to was interpolated for an additional 50 loci each of which had optimize order and a stepwise elimination of weakly sup- been assigned to an interval of less than 10 megabases. The ported loci to identify a conservative set of reliably ordered resulting composite map is on the physical scale with a reso- (framework) markers. The genetic map was combined with lution of 1.5 megabases. In the future these methods may be other evidence from the literature and the on-line genome used to incorporate locations from linkage, contigs, radiation data base (GDB) (9) by using the location data base program hybrids, restriction fragments, and somatic cell maps. Dense, (ldb) (10). This integrates these partial maps into a composite reliable, and well-documented maps are essential for long- map that conveys both order and physical location. A sum- range sequencing and to local and clone disease genes. mary map comprises the ordered loci and composite location together with the genetic map, cytogenetic and otherphysical Chromosome 1 is the largest in man and it provided the first data, and any homologies in the mouse (see Table 3). Locus autosomal linkage and physical maps (1) and radiation hybrid symbols were obtained from GDB (9) and Human Gene map (2). The Centre d'Etude du Polymorphisme Humain Mapping 10.5 (11). (CEPH) consortium map recognized 58 reliably ordered framework loci and an additional 43 locally unordered loci RESULTS whose regional assignment was indicated (3). A number of TMe Framework Map. A map ofloci for which order is well loci mapped in other samples are given in the LODSOURCE supported by linkage is termed a framework map (4). Such a data base (4). They include blood groups, isozymes, and map is useful for interval location ofdisease loci. A subset of diseases not represented in the CEPH sample, as well as such loci selected through a gene mapping committee as additional data on other markers. Multipoint analysis neglect- suitable for low-resolution linkage studies are termed refer- ing interference and typing errors requires assembly of raw ence loci. Twenty-one loci have been designated as reference data from hundreds of reports over nearly 40 years, which is markers for chromosome 1 (12). They all have heterozygos- clearly not feasible. Here we use multiple pairwise analysis ities >0.50, have been placed in the genetic map by at least of sex-specific logarithm-of-odds (lod) scores with allowance two independent studies, and have been physically mapped for interference and typing errors to produce a genetic map on hybrid panels or by in situ hybridization. They are highly of 127 loci, which is then integrated with other data into a informative and span nearly the whole chromosome. Such composite map of 177 loci, which conveys physical location. gold-star loci have not, however, been useful in other orga- nisms, because high-resolution mapping requires dense MATERIAL AND METHODS markers (10) and technical advances replace one type of hypervariability by another (13). Local support is measured The LODSOURCE data base accumulates data as standard lod by the lod ofthe best order against the most likely interchange tables for males, females, and unspecified sex. Since the with an adjacent locus, and interval support is measured by object of linkage analysis in man is to produce sex-specific the lod of the best order against the most likely insertion in maps agreeing in order but not distance, we factored bivariate another interval. Therefore interval support is always less lod scores by sex, Z(Om, Of) = Z(Om) + Z(Of), where Z(O) = than or equal to local support. Keats et al. (4) suggested that log10 [P(O)/P('/2)]. Here Z denotes a lod, 0 a recombination a framework map by multipoint analysis should have interval fraction, and P(O) the probability ofa sample as a function of support (and therefore local support) of at least 3, corre- 0, and m and f are males and females, respectively. Lod sponding to odds of 1000:1, which by a posterior probability scores are additive over samples and may be summarized for argument is required to assert significant linkage for two each pair of loci by no more than six numbers: Om, ±m, Of, random markers. They recognized that this argument does ou, Zu, where the caret indicates a maximum likelihood not apply to two markers known to be on the same chromo- estimate and u denotes unspecified sex. Bivariate lod scores some, but they expressed the hope that an extreme signifi- were calculated for CEPH data (3) by the CRIMAP program (P. cance level could compensate for the sensitivity ofmultipoint Green, personal communication) and factored into male and analysis to typing errors. Subsequently, it has been shown female entries by the LODS program (5). All sources except that multiple pairwise analysis is less sensitive to typing CEPH were taken from the LODSOURCE data base, which errors, especially with error filtration as performed by the derives maximum likelihood estimates by interpolation in MAP9o program (7). Accordingly we have used a local support The publication costs ofthis article were defrayed in part by page charge Abbreviations: CEPH, Centre d'Etude du Polymorphisme Humain; payment. This article must therefore be hereby marked "advertisement" GDB, genome data base; lod, logarithm ofodds; cM, centimorgan(s); in accordance with 18 U.S.C. §1734 solely to indicate this fact. Mb, megabase(s). 4598 Downloaded by guest on September 26, 2021 Medical Sciences: Collins et al. Proc. Natl. Acad. Sci. USA 89 (1992) 4599 of at least 1 to define framework loci by multiple pairwise Table 2. Estimates of framework parameters analysis. Framework loci may also be defined on physical Map length, cM evidence (14). To construct a comprehensive genetic map the CEPH consortium map of chromosome 1 was used to provide Arm p Male Female K an initial framework (3); AMY2B, SPTAI, and D1S8 were p 0.009 0.236 117.3 210.1 1.79 excluded because, at this stage, the MAP90 program did not q 0.007 0.253 111.7 164.5 1.47 support the consortium final order for these loci. The re- p + q 0.008 0.309 233.7 390.8 1.67 maining loci were inserted at their most likely locations in this E, Error frequency; p, mapping parameter; K, ratio ofgenetic map map of 55 loci. A final conservative framework map with a lengths in females and males. minimum local support of 1 with the inclusion of the 21 reference loci was obtained by using an algorithm for step- from chiasmata, which is 201 cM from arms with a terminal wise elimination of loci with the lowest local support. This chiasma (16) and 194 cM for all arms (17). It seems likely that process gave a map of 49 loci from DIZ2 to D1568 that is in conservative enumeration of chiasmata omits a fraction that close agreement with the consortium map except in regions may be as great as 16%, and therefore the distribution of where there is a large gap between reference loci. For chiasmata along the unbanded meiotic chromosome should example, in the 50 centimorgans (cM) that separate D1561 be taken as only a rough indication of the genetic map. It and DIS81 on the male map our algorithm chooses the highly remains true that a male map much in excess of the chiasma supported loci D1565, DIS84, and SNRPE in preference to map raises a suspicion of inadequate allowance for typing F13B and DS5S3. Clearly, gold-star loci are not unique and errors or interference. are subject to continual revision by new evidence and/or The Composite Map. Chromosome 1 has poor physical consensus. information, with few contigs, no long-range restriction frag- Since order in a comprehensive genetic map is locally ment map, no standard somatic cell panel defining regions, unreliable, framework loci should provide better estimates of and no radiation hybrid map since the pioneer work on a few error frequency, mapping parameter, and sex-specific arm loci (2). However, cytogenetic assignment provides coarse lengths. From replicate typing the error frequency has been localization that can be used to project the genetic map into estimated as 0.006 (54 discordancies among 4205 duplicate the physical map. Therefore this fragmentary evidence may samples) (3). The MAP90 program agrees closely, with an error be integrated into a composite map that will converge to a frequency of 0.008 0.001 (Table 1).