APPENDIX

Please call my attention to errors of omission or commission. V.A .M.

Victor A. McKusick, M.D. The Johns Hopkins Hospital Baltimore, MD 21205 October 15, 1986

THE HUMAN GENE MAP

The following information, updated periodically since 1973, is based in large part on eight International Workshops on Human Gene Mapping. The first was organized by Dr. Frank Ruddle and held in New Haven in June 1973. The second, known as the Rotterdam Conference, was organized by Dr. Dirk Bootsma and held in The Netherlands in July 1974. The third, organized by Dr. Victor McKusick, was held in Baltimore in October 1975. The fourth, organized by Dr. John Hamerton, was held in Winnipeg in August 1977. The fifth, organized by Dr. John Evans, was held in Edinburgh in July 1979. The sixth, organized by Dr. Kare Berg, was held in Oslo in June-July 1981. The seventh, organized by Dr. Robert Sparkes, was held in Los Angeles in August 1983. The eighth, organized by Dr. Albert de la Chapelle, was held in Helsinki in August 1985. The first six were sponsored exclusively by the National Foundation-March of Dimes (now March of Dimes Birth Defects Foundation) which publishes the proceedings as part of its Birth Defects: Original Article Series. The proceedings also appear in Cvtogenetics and Cell Genetics (Table I). The number of loci mapped by the time of each workshop and updated counts are given in Table II. The numbers of mapped loci can be compared with the counts of total loci in Mendelian Inheritance in Man, as given in Table III.

TABLE I

Publication of Proceedings of Human Gene Maooin~ Workshoos

BD:OAS Cytogenet. Cell Genet. HGMI New Haven (1973) X(3):1-216, 1974 1..~3:1-216, 1974 HGM2 Rotterdam (1974) XI(3):1-310, 1975 1..44:162-480, 1975 HGM3 Baltimore (1975) XII(7):1-452, 1976 1_.66:1-452, 1976 HGM4 Winnipeg (1977) XIV(4):l-730, 1978 22--1-730, 1978 HGM5 Edinburgh (1979) XV(11):1-236, 1979 25:2-236, 1979 HGM60s lo (1981) XVIII(2):1-343, 1982 32:1-343, 1982 HGM7 Los Angeles (1983) XX(2):1-666, 1984 37--1-666, 1984 HGM8 Helsinki (1985) XXI(4):1-832, 1985 40--1-832, 1985

Previous editions of this newsletter appeared in Clinifal Genetics 22: 359-391, 1982 (Dec.); 2__55: 89-123, 1984 (Jan.); 27-- 207-239, 1985 (Feb.); and 29.__'. 545-588, 1986 (June).

Table of Contents

This newsletter has 3 pictorial representations of the human gene map: Fig. 1, A-D. The full map, following p. 1. See Key for symbols, beginning on p. 5 Fig. 2, A-D. The morbid anatomy of the human genome, following p. 75 Fig. 3, The mitochondrial chromosome, following p. 77

Chromosome by chromosome, the genes located on each are listed, as follows: I. A. The autosomes, No. 1 to No. 22: pp. 26-61

B. Unassigned linkage groups: pp. 62-63 II. The Y chromosome: pp. 63-64

III. The X chromosome: pp. 65-67 IV. The morbid anatomy of the human genome: pp. 68-75 V. The Oxford Grid: homology of synteny in mouse and man: p. 76

VI. The mitochondrial chromosome: p. 77

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TABLE II

Number of Loci Assigned at Each of the Eight Human Gene MaDDing Workshoos With Update of October 15. 1986

Conference Number of autosomal assignments* X chromosome assignments**

Confirmed Provisional Tentative ('in limbo"; inconsistent)

Total Confirmed In Limbo

New Haven (1973) 31 28 5 64 88 67 Rotterdam (1974) 48 32 6 86 91 70 Baltimore (1975) 72 46 7 125 95 80 Winnipeg (1977) 83 82 11 176 102 96 Edinburgh (1979) 123 87 20 230 112 I01 Oslo (1981) 180 120 45 345 116 118 Los Angeles (1983) 247 161 80 488 118 136 Helsinki* (1985) 351 216 66 633 123 157 October 15, 1986 388 273 69 730 130 164

*(plus 300 anonymous DNA segments, 82 antigens, 19 O'FarreU protein spots, all of unknown function, 19 pseudogenes, 18 "like" genes, and 63 fragile sites, to a grand total, for autosomes, of 1134.) **(plus 186 DNA segments, 4 protein spots, 4 antigens, 3 fragile sites, 25 pseudogenes and 20 "like" genes, to a grand total, for the X, of 522.)

TABLE III

Number of loci identified mainly by mendelizing phenotypes*w From McKusick: Mendelian Inheritance in Man

Mendelian Inheritance in Man

Phenotype Verschuer 1966 1968 1971 1975 1978 1 9 8 3 1986"** 1958"* (lst ed.) (2nd ed.) (3rd ed.) (4th ed.) (Sth ed.) (6th ed.) (7th ed.)

Autosomal Dominant 285

Autosomal Recessive 89

X-Linked 38

Total 412

Grand Total 412

269(+568) 344(+449) 415(+528) 583(+635) 736(+753) 934(+893) 1172(+1029)

237(+294) 280(+349) 365(+418) 466(+481) 521(+596) 588(+710) 6t0(+810)

68(+51) 68(+55) 86(+64) 93(+78) 107(+98) 115(+128) 124(+162)

574(+913) 692(+853) 866(+1010)1142(+1194~364(+1447)1637(+1731)1906(+2001)

1487 1545 1876 2336 2811 3368 3907

*Numbers in parentheses refer to loci not fully identified or validated. w loci identified by molecular and cellular genetic methods are included despite the lack of mendelian variation in phenotype. **Lehrbuch de.....gr Human~enetik (Munich: Urban & Schwartzenberg, 1958). ***7th edition closed March 1, 1986. Numbers as of Oct. 15, 1986: AD 1234(+1053); AR 624(+818); X 130(+164); Total 1988(+2035); Grand Total 4023.

1128

The methods for mavnin~ ~enes (see Table IV for counts) are symbolized as follows:

1. A ffi in situ DNA-RNA or DNA-DNA annealing ('hybridizationS), e.g., ribosomal RNA genes to acrocentric chromosomes; kappa light chain genes to chromosome 2.

2. AAS ffi deductions from the amino acid sequence of proteins; e.g., linkage of delta and beta hemoglobi'l loci from study of hemoglobin Lepore. (Includes deductions of hybrid protein structure by monoclonal antibodies, e.g., close linkage of MN and SS from study of Lepore-like MNSs blood group antigen.)

3. C ffi chromosome mediated gene transfer (CMGT), e.g., cotransfer of galactokinase and thymidine kinase. (In conjunction with this approach fluorescence-activated flow sorting can be used for transfer of specific chromosomes.)

4. Ch = chromosomal change associated with particular phenotype and not proved to represent linkage (Fc), deletion (D) or virus effect (V); e.g., loss of 13q14 band in some cases of retinoblastoma. (~Fragile sites," observed in cultured cells with or without folate-deficient medium or BrdU treatment, fall into this class of method, e.g., fragile site at Xq27.3 in one form of X-linked mental retardation. Fragile sites are useful as markers in family linkage studies, e.g., FSI6q22 and haptoglobin.)

5. D = deletion mapping (concurrence of chromosomal deletion and phenotypic evidence of hemizygosity), trisomy mapping (presence of three alleles in the case of a highly polymorphic locus), or gene dosage effects (correlation of trisomic state of part or all of a chromosome with 50% more gene product). Examples: acid phosphatase-1 to chromosome 2; glutathione reductase to chromosome 8. Includes DNA dosage, e.g., fibrinogen loci to 4q2.

6. EM = exclusion mapping, i.e., narrowing the possible location of loci by exclusion of parts of the map by deletion mapping, extended to include negative led scores from families with marker chromosomes and negative led scores with other assigned loci; e.g., support for assignment of MNSs to 4q.

7. F ffi linkage study in families; e.g., linkage of A B e blood group and nail-patellasyndrome. (When a chromosomal heteromorphism or rearrangement is one trait, Fc is used; e.g., Duffy blood group locus on chromosome 1. When a DNA polymorphism is one trait, Fd may be used; e.g., Huntington disease on chromosome 4.)

8. H ffi based on presumed homology; e.g., assignment of LDHC to 12p. Includes Ohno's law of evolutionary conservatism of X chromosome in mammals.

9. HS ffi DNA/cDNA molecular hybridization in solution ( 'Cot analysis'), e.g., assignment of Hb beta to chr. 11 in derivative hybrid cells.

10. L = lyonization, e.g., OTC to X chromosome.

1 I. L D ffi l inkage d isequi l ibr ium, e.g., beta and delta globin genes (HBB, HBD).

12. M = Microcell mediated gene transfer (MMGT), e.g., a collagen gene (COL 1A 1) to chromosome 17.

13. OT ffi ovarian teratoma (centromere mapping), e.g., PGM3 and centromere of chr. 6.

14. R = irradiation of cells followed by "rescue" through fusion with nonirradiated (nonhuman) cell (Goss-Harris method of radiation-induced gene segregation); e.g., order of genes on Xq. (Also called cotransference. The complement of cotransference = recombination. Cotransference can be observed also when mitotic chromosomes are used for activated- oncogene-mediated cellular transformation, e.g., Porteous et al., HGM8.)

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15. RE = Restriction endonuclease techniques, e.g., fine structure map of the beta-globin cluster (HBBC) on 1 lp; physical linkage of 3 fibrinogen genes (on 4q) and APOAI and APOC3 (on l i p ) .

REa = combined with somatic cell hybridization, e.g., N A G (HBBC) to 1 lp. REb = combined with chromosome sorting, e.g., insulin to lip.

Includes Lebo's adaptation (dual laser chromosome sorting and spot blot DNA analysis), e.g., MGP to l l q .

16. S = "segregation" (cosegregation) of cellular traits and chromosomes (or segments of chromosomes) in particular clones from somatic cell hybrids, e.g., thymidine kinase to chromosome 17. When with restriction enzyme, REa; with hybridization in solution, HS.

17. V ffi induction of microscopically evident chromosomal change by adenovirus (probably represents change comparable to "puffing" in insects; accompanied by activation of kinases), e.g., adenovirus 12 changes on chr. 1 and 17.

18. X / A = X-autosome translocation in female with X- l inked recessive disorder, e.g., assignment of Duchenne muscular dystrophy to Xp21.

TABLE IV

Number of Autosomal Loci Mavved bv the Several Methods (October 15, 1986)

Method NO, 0f loci manoed

Somatic cell hybridization (S, REa, HS, M) - 554 Family linkage study (F, Fc, Fd) - 235 Ln situ hybridization ( A ) - 210 Dosage effect (D) 85 Chromosome aberrations (Ch) 65 Restriction enzyme fine analysis (RE) 41 Homology of synteny (H) 50 Radiation induced gene segregation (R) 17 Others (LD, OT, EM, V, REb, C, AAS) - 77 Total (many mapped by 2 or more methods) 1334

The certainty with which assignment of loci to chromosomes or the linkage between two loci has been established has been graded into the following classes:

C =confirmed - observed in at least two laboratories or in several families (NOT USED IN THE FOLLOWING GLOSSARY OF GENE SYMBOLS BUT CAN BE ASSUMED WHEN ONE OF THE OTHER SYMBOLS IS NOT GIVEN).

P = provisional - based on evidence from one laboratory or one family.

I = inconsistent - results of different laboratories disagree.

L = l i m b o g r o u p - evidence not as strong as provisional, but included for heuristic reasons. (Same as "tentative" in other terminology.)

The five digit numbers given here are entry numbers in McKusick 's Mendelian Inheritance in Man (7th ed., 1986, Johns Hopkins Univ. Press). Documentation on linkages and assignments is referenced in the entries indicated. The banding numerology is that of ISCN 1985: A._E International System for Human ~?vto~enetic Nomenclature. Birth Def. Orig. Ar_..At. Ser. XI__~I (1): 1-117, 1985.

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B. Linked autosomal loci for which assignment to a specific chromosome has not yet been achieved (Unassigned Linkage Groups; ULGs).

The tightness of the linkage is stated in general terms defined as follows:

v -- very close; recombination less than 2% (NR -- no recombinant observed) c = close; recombination 2 - 6% m = medium; recombination 6 - 22% 1 = loose; recombination more than 22% ? = lods 2.0-3.0

. Phenylthiocarbamide taste, PTC (17120) (m, F) Kell blood group, K,KEL (11090) Hyperreflexia, HRX (14529)

(Spence: Hum. Genet. 67: 183-186, 1984. All published data= but evidence of heterogeneity.)

lod -- 8.94 at theta 0.14,

. Complement component-6, C6 (21705) Complement component-7, C7 (21707) (v, F)

(C6 and C7 linked in dog, marmoset. Two C7 loci in dog. In man, C6 and C7 genes physically close by DNA studies (RE). Linkage supported by observation of combined deficiency).

3. Ii blood group, II (11080) Congenital cataract, CCAT (21250) (?c, F)

. Epidermolysis bullosa progressiva, EBR3 (22650) Hypoacusis (HOAC; a recessive partial deafness) (22070) (?c, F) ?Red hair, RHA (26630)

. Cerebellar ataxia, a recessive form, CPD3 (21320) Tyrosinase-negative albinism, ATN (20310) (?c, F)

(From homology to tyrosine-negative albinism in the mouse, which is linked to the beta-globin cluster (ScM apart) and to malic enzyme, mitochondrial (4cM apart), on mouse chromosome 7, this linkage pair in man might be on either 1 lp or 6p).

. Marinesco-Sjogren syndrome, MSS (24880) Hypergonadotropic hypogonadism,HRGHG (23832) (m, F)

(Lod score more than +30; however, HRGHG probably pleiotropic effect of MSS).

7. The chromosomal location of the GPTI linkage group is not certain, with assignment claimed particularly for chromosomes 8 and 16, but also very weakly for chromosome 13 (HGM7). (Assignment to 10 is disproved.) This linkage group is as follows:

Glutamate pyruvate transaminase, soluble red cell, GPTI (13820) Macular dystrophy, atypical vitelliform, VMDI (15384) - 5cM from GPTI Epidermolysis bullosa, Ogna type, EBSI (13195) - closely linked to GPT1 (Linkage of breast cancer, 11448, to GPTI is unsubstantiated and perhaps disproved).

. Complement component-4 binding protein, C4BP (12083) (all r, F) Complement component C3b, receptor for; C3BR, CR1 (12062) Complement component C3d, receptor for; C3DR (12065) Complement factor H, CFH (13437)

(In MHC in mouse, but in man not linked to MHC (on 6p) or to C3 (on 19p), probably on human chromosome 1 (E. Solomon, p.c.).) Factor H deficiency is observed with IgA nephropathy.

1188

63

. Restriction mapping indicates that type I (14803) and type II (14804) keratin genes are linked as well as glycine-rich keratins and keratins without glycine-rich regions. All keratin genes (at least 20 in number) may be in one region of the genome.

10. Xeroderma pigmentosum, group D, XPD (27873) Trichothiodystrophy (24217) (?c,F)

For a collection and collation of published linkage data, see the following: Keats, B.J.B., Morton, N.E., Rao, C.C., and Williams, W.R.: A Source Book for Linkage in Man. Baltimore: Johns Hopkins University Press, 1979; Keats, B.J.B.: Linkage and Chromosome MaDoing in Man. Honolulu: University Press of Hawaii, 1981.

II. QENE MAP OF THE Y CHROMOSOME (See Goodfellow et al.: The human Y chromosome. J. Med. Genet. 22." 329-344, 1985.)

A. From the study of variant Y chromosomes, a factor (or factors) which determines the differentiation of the indifferent gonads into testes is known to be located on the Y chromosome, probably on the short arm; this may be called to~tis determining factor (TDF). (See Davis, i. Med. Genet. 18:161-195, 1981.) Translocation of this locus to Xp as the cause of XX males was suggested by Ferguson-Smith (1966) and found confirmation in several observations (e.g., Page et al., Am. J. Hum. Genet. 136: 150s, 1984). Location of TDF near the centromere was suggested by Davis (1O~, qig.) and others; translocated to an X in XX males may indicate a somewhat more distal location.

B. Histocompatibility antigens determined by the Y chromosome were first found in the mouse (Eichwald, E.J., and Silmser, C.R.: Transolant Bull. 2: 148-149, 1955; see review by Gasser, D.L. and Silver, W.K.: Genetics and immunology of sex-linked antigens. Adv. Immun. 15: 215-217, 1972) and are now known also in the rat, guinea pig, and many other species. Their existence in man was first shown by the fact that mouse antisera react with human male lymphocytes but not with female lymphocytes (Wachtel, S.S., Koo, G.C., Zuckerman, E.E., Hammerling, U., Scheid, M.P., and Boyse, E.A.: Serological cross reactivity between H-Y (male) antigens of mouse and man. PNA$ 711.: 1215-1218, 1974). The strong likelihood that the locus that determines heterogametic sex determination and that for the H-Y antigen are one and the same was suggested by Wachtel et al. (Possible role for H-Y antigen in human males with two Y chromosomes. Nr Eng. i. Med. 293: 1070-1072, 1975.) The hormone-like action of the H-Y antigen in the bovine freemartin was discussed by Ohno et al. (Nature 261: 597, 1976). See also Wachtel et al., Nr Eng. i. Med. 29~: 750, 1976. H-Y and TDF may be one and the same. Like HLA, H-Y is a differentiation antigen. (See Wachtel: Where is the H-Y structural gene? Gr 22-- 3-4, 1980.) (At the 1986 Cold Spring Harbor Symposium, 6 speakers discussed the Y chromosome at length, but H-Y was not once mentioned.) From the study of XX males, it can be concluded that the H-Y determinant on the Y (whatever its nature) and TDF are separate entities and not closely situated (Simpson, E.: The H-Y antigen and sex reversal. Cell 4..~4: 813, 1986).

C. A pseudoautosomal segment (PAS) of distal Yp and distal Xp (between which crossing-over occurs) has been suspected from microscopic observations and has found confirmation in the study of polymorphic DNA markers. It appears that TDF is just proximal to PAS; that in PAS there is one, but only one, obligatory crossingover. The following order has been observed: Ypter - DXYSI4 - 50% recombination with sex - DXYSI5 - 35.5% - DXYSI7 - 11.5% - MIC2 - 2.7% - TDF. These values are strictly additive indicating no double crossovers. Thus, the sequence can be written: Ypter - DXYSI4 - 14.5% - DXYSI5 - 24% - DXYSI7 - 8.8% - MIC2 - 2.7% - nonexchanging segment of Yp containing TDF. The exact

location of TDF in relation to the centromere, whether close to it or farther toward pter or even on proximal Yq has been uncertain. Inversion polymorphism of the part of the Y that does not participate in recombination might be expected to be well tolerated. The MIC2Y (see 31347)gene is the first Y chromosome gene for which a gene product was identified, the first gene proved to have pseudoautosomal inheritance and the first gene proved to escape

1189

64

lyonization.

D. The existence of factors controlling spermatogenesis on the nonfluorescent part of the long arm of Y (distal part of Yql l ) was suggested by study of 6 men with deletion of this segment and azoospermia (Tiepolo, L. and Zuffardi, O., Hum. Genet. 34-- 110-124, 1976). This has been called azoospermia third factor (symbolized Sp-3), or more recently (HGM8), AZF (for azoospermia factor).

E. That one or more genes concerned with stature are on the Y chromosome is suggested by the comparative heights of the XX, XY and XYY genotypes; that the effect of the Y chromosome on stature is mediated through a mechanism other than androgen is suggested by the tall stature of persons with XY gonadal dysgenesis (30610). See also the argument, from XO and XXY cases, that genes determining slower maturation must be on the Y (Tanner, J.M., Prader, A., Habich, H. and Ferguson-Smith, M.A.: Genes on the Y chromosome influencing rate of maturation in man. Skeletal age studies in children with Klinefelter's (XXY) and Turner's (XO) syndromes. Lancet II: 141-144, 1959). The postulated locus is symbolized STA (for "stature"). Yamada et al. (Hum. Genet. 58:268-270, 1981) found a correlation between the length of heterochromatic band Yql2 and height. The STA locus may be identical to the TSY (or GCY) locus.

F. Alvesalo and de la Chapelle (Ann. Hum. Genet. 43: 97-102, 1979; HGM5, Edinburgh, 1979) suggested, on the basis of tooth size in males of various Y chromosome constitutions, that a Y-chromosomal gene controlling tooth size is independent of the testis-determining gene and is carried by Yql I (symbolized TS for "tooth size," or, more recently in HGM8, GCY for "growth control Y"). See Alvesalo and Portin, Am. J. Hum. Genet. 32: 955-959, 1980; Alvesalo and de la Chapelle, Ann. Hum. Genet. 54:49-54, 1981. The dental growth factors are thought to coincide with determinants of stature.

G. HGM8 (Helsinki, 1985) catalogued at least 22 seemingly low copy number anonymous DNA segments mapped exclusively to specific regions of the Y chromosome, as well as at least 23 DNA segments that map to both the Y and the X, some that map to both to the Y and to an autosome, and some repetitive DNA segments that map to the Y exclusively or to both the Y and the X.

H. Repetitive sequences located exclusively or predominantly to the Y chromosome (e.g., Kunkel, Smith, Boyer, Biochemistry 18: 3343-3353, 1979) map to the heterochromatic portion of Yq and are presumably genetically inert because persons lacking these are phenotypically normal and normally fertile.

An argininosuccinate synthetase pseudogene is on the Y (Daiger et al., Nature 298: 682, 1982), as is also an actin pseudogene (Heilig et al., EMBQ J. 3:1803, 1984).

J. The only specific structural gene confidently identified on the Y chromosome is that homologous to the X-linked gene for surface antigen MIC2 (Goodfellow et al., Nature 298: 346, 1983) i.e., this is the sole known Y-specific gene product; the locus, termed MIC2Y, is located in the Ypter-Yql 1.2 segment. MIC2X is an homologous locus at Xp22.32 (Buckle et al., Nature 317: 739, 1985). See MIM 31347. (See Fig. 1 of Polani, Hum. Genet. 60: 207, 1982, and of Burgoyne, Hum. Genet. 61: 95, 1982, for suggested homologous segment of X and Y.) Polymorphisms in the homologous segment of X and Y show "pseudoautosomal" inheritance (Cooke et al., Nature 317: 687, 1985; Simmler et al., Nature 317: 692, 1985).

K. According to the classical model (using the term of Goodfellow et al., 10r tit..), the Y chromosome has been thought to have several subregions: (1) an X-Y homologous meiotic pairing region occupying most of Yp and perhaps including a pseudoautosomal region of X-Y exchange; (2) a pericentric region containing the sex determining gene(s); and (3) a long arm heterochromatic genetically inert region. As noted above, some recent findings support the classical model, whereas others refute it. Molecular studies indicate that Yp contains many sequences not homologous to Xp but with homology to Yq, Xq, or an autosome.

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V. THE OXFORD GRID

(Courtesy of Searle, Peters, Lyon, Evans, Edwards, and Buckle [to be published in Clinical Genetics]. Earlier version published by Buckle et al., Clin. Genet. 26:1-11, 1984.)

In this ingenious diagram, the length of each line represents the proportionate length of the given chromosome of mouse or man. The triangles or circles indicate the chromosomal location of a given homologous locus in mouse and man. Triangles point down or up depending on whether the locus is on the short arm or the long arm, respectively, of the human chromosome. Circles indicate that the arm location is unknown. The open symbols represent additions since the 1984 version. Note that for all except human chromosome 13, at least 2 loci on the given human chromosome are also syntenic in the mouse. Note that longer human chromosomes show a tendency to homology of synteny with larger mouse chromosomes; conversely, smaller human chromosomes tend to show homology with smaller mouse chromosomes. This diagram is useful in predicting the location of a human gene whose murine homolog has been mapped.

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77

VI. THE MITOCHONDRIAL CHROMOSOME (Chromosome M or Chromosome 25)

Each mitochondrion contains several circular chromosomes. The most important function of the mitochondria is synthesis of ATP by the process of oxidative phosphor'.~lation (OXPHOS). OXPHOS involves 5 multi-polypeptide enzyme complexes in the mitochondrial inner membrane. The biogenesis of 4 of these 5 complexes is under the combined control of nuclear DNA and mitochondrial DNA (mtDNA). At least 69 separate polypeptides are known to be required for OXPHOS; only 13 of them are coded by mtDNA.

The 16,569 basepairs of the mitochondrial chromosome are the equivalent of 5,523 codons. Most of the mtDNA serves a coding function. The genes contain no intervening sequences, and little in the way of flanking sequences is present. The ribosomal and transfer RNAs are those involved in the synthesis of protein in the mitochondrion. Of the 22 tRNAs, 14 are coded on the L (light) strand. For all but 1 of the 13 reading frames, the function of the specific protein coded is known. The mtDNA code differs from that of the nuclear DNA and the genetic code of any presentday prokaryote. UGA codes for tryptophan (not termination), AUA codes for methionine (not isoleucine), and AGA and AGG code for termination (not arginine). The mitochondrial genome is transcribed as a single mRNA transcript which is subsequently cleaved into its several component genes.

Mitochondrial inheritance ('cytoplasmic inheritance' in the old terminology) is exclusively matrilineal. Restriction fragment length polymorphisms (RFLPs) are known in mitochondrial DNA as in nuclear DNA. Mitochondrial restriction patterns can be used to construct a biological history of the human species.

Whereas each nuclear chromosome is present in only 2 copies per cell at the most, the mitochondrial chromosome is present in thousands of copies. The behavior of a mitochondrial mutation in inheritance might be expected, therefore, to be galtonian rather than mendelian.

In cultured cells, chloramphenicol resistance is demonstrably the result of mutation in the mtDNA gene for 16S rRNA. Indeed, the specific nucleotide changes have been identified. Disorders that are thought to involve mitochondrial mutation include Leber optic atrophy, which is often associated with 'neurodegenerative' disorders (see 30890), infantile bilateral striatal necrosis (IBSN), and myoclonic epilepsy with 'ragged red fibers' (MERRF).

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(nucleotlde pair) GENE LOCATION

(nucleotlde pair)

(L-strand promoter (major H-strand promoter (minor L-strand start site tRNA phenylalanine (minor H-strand start site 12S rRNA tRNA valine 16S rRNA tRNA leucine~UUR) NADH dehydrogenase subunit 1 tRNA isoleucine tRNA glutamine tRNA methionine (including fMET) NADH dehydrogenase subunit 2 tRNA tryptophan tRNA alanine tRNA asparagine (origin of L-strand replication tRNA cysteine tRNA tyrosine cytochrome c oxidase subunit I tRNA serine

about 392-435) about 545-567)

561) 577-647

about 645) 648-1601

1602-1670 1671-3229 3230-3304 3307-4262 4263-4331 4329-4400 4402-4469 4470-5511 5512-5576 5587-5655 5657-5729

5729-5805) 5761-5826 5826-5891 5904-7444 7445-7516

tRNA asparagine cytochrome c oxidase subunit II tRNA lysine ATPase subunit 8 (URF A-L) ATPase subunit 6 cytochrome c oxidase subunit Ill tRNA glycine NADH dehydrogenase subunit 3 tRNA arginine NADH dehydrogenase subunit 4L NADH dehydrogenase subunit 4 tRNA histidine tRNA serine (AGY) tRNA leucine (CUN) NADH dehydrogenase subunit 5

7518-7585 7586-8262 8295-8364 8366-8572 8527-9207 9207-9990

9991-10058 10059-10404 10405-1 0469 1 0470-10766 10760-12137 12138-12206 12207-12265 12266-12336 12337-14148

NADH dehydrogenase subunit 6 (on L) 14149-14673 tRNA glutamic acid (L-strand) 14674-14742 cytochrome b 14747-15887 tRNA threonine 15888-15953 tRNA proline (L-strand) 15955-16023 (membrane attachment site about 15925-499)

1208

Author Index

A

Aaronson, S.A., 959 Abraham, J.A., 657 Aggarwal, B.B., 597 Akiyama, T., 977 Albers, J.J., 403 Almaldi, I., 67 Alt, F.W., 931 Amphlett, G., 543 Anderson, L.A., 169 Andrews, P., 419 Angelini, G., 803 Antonarakis, S.E., 185, 371 Armentano, D., 1073 Arveiler, B., 195 Attardi, G., 103 Axel, R., 703 Ayres, T.M., 499 Azizov, M.M., 611

B

Baehner, R.L., 177 Baer, R., 923 Bakker, E., 353 Ball, E., 803 Ball, G.D., 571 Ball, S.P., 337 Banting, G.S., 205 Barbacid M., 983 Barker, D.F., 317 Barlow, D.P., 131 Barranger, J.A., 1047 Bartholdi, M.E, 159 Bates, G., 309 Battey, J.E, 843 Beaudet, A.L., 1027 Bell, G., 309 Bell, J., 309 Bell, J.I., 75 Belmont, J.W., 1065 Bennett, D.D., 967 Bennett, W.E, 551 Berdoz, J., 67 Berkner, K., 531 Bernardi, G., 479 Bernardi, G., 479 Bernstein, A., 1083 Bernstein, Y., 381 Berte, C., 67 Bertelson, C.J., 349 Beutler, B., 625 Beutler, E., 1041 Bhatia, K., 433 Birchmeier, C., 993 Bishop, C., 237 Blaese, R.M., 1073 Blair, D.G., 967 Bodmer, W.F., 1 Bodrug, S., 345 Boehm, C.D., 371 Boldyreva, E.F., 611 Boosman, A., 679 Bootsma, D., 91 Bordignon, C., 1073

Botstein, D., 49 Boucekkine, C., 237 Bowcock, A.M., 411 Boyles, J.K., 821 Braman, J.C., 317 Bringman, T.S., 649 Brissenden, J.E., 855 Brooks, B.J., 843 Brouckaert, P., 587 Brown, B.G., 403 Brown, M.S., 811 Browne, J.K., 693 Bruns, G.A.P., 299, 837 Brunzell, J.D., 403 Bucci, C., 411 Buchwald, M., 325 Builder, S.E., 551 Buluwela, L., 923 Busby, S., 531 Bystrov, N.S., 611

C

Caccia, N., 797 Camerino, G., 195 Cantor, C.R., 115, 123 Capecchi, M.R., 1101 Capra, J.D., 803 Carrano, A.V., 159 Casanova, M., 237 Caskey, C.T., 1065, 1115 Cate, R.L., 641 Cavalli-Sforza, L.L., 411 Cavenee, W.K., 829 Cerami, A., 625 Chakravarti, A., 185 Chambon, P., 751 Chang, S.M.W., 1065 Chao, C.-Y., 1027 Cheng, S.V., 359 Chess, L., 703 Chizzonite, R., 631 Chloupek, R.C., 551 Chomyn, A., 103 Chorney, M.J., 123 Choudary, P.V., 1047 Chumakov, A.M., 611 Chuvpilo, S.A., 611 Clapham, P.R., 703 Clark, S.C., 685 Clauser, E., 773 Cohen, A.M., 693 Cole, ES., 177 Collen, D., 563 Colletti, C.A., 349 Collins, ES., 123 Concannon, P., 785 Conneally, P.M., 359 Cooke, H.J., 213 Copeland, T., 967 Coussens, L., 713 Coutelle, C., 337 Craig, A., 131 Cram, L.S., 159 Croce, C.M:, 891

Curnutte, J.T., 177 Cuttitta, F., 843

D

Dafni, N., 381 Dalgleish, A.G., 703 Danciger, E., 381 Darling, S.M., 205 Davie, E.W., 509, 531 Davies, K.A., 309 Davies, K.E., 337 Davis, C.G., 811 Davis, L.M., 867 de la Chapelle, A., 249 Dean, M., 967 Deaven, L.L., 159 Deeb, S., 403 Deka, N., 473 Delannoy, M.R., 943 Denney, D., 75 DePinho, R., 931 Depper, J.M., 731 Derynck, R., 649 Deschamps, J., 949 Devos, R., 587 Diaz, M.O., 899 Dick, J.E., 1083 DiLella, A.G., 395 Disteche, C., 237 Dobrynin, V.N., 611 Donahoe, P.K., 641 Donahue, R.E., 685 Donis-Keller, H., 317 Donlon, T., 299 Doolittle, R.F., 103, 447 Dorkins, H.R., 337 Dowling, C.E., 371 Dozy, A.M., 1033 Dull, T., 713 Dunckley, H., 83

E

Eaton, D., 365 Edery, M., 773 Eglitis, M., 1073 Egrie, J.C., 693 Ehrich, E., 131 Ellis, L., 773 Elroy-Stein, O., 381 Erikson, J., 891 Erlich, H., 263 Estivill, X., 309 Estrov, Z., 1083 Evans, R.M., 759

F

Failor, A., 403 Faloona, E, 263 Fantes, K.H., 571 Farrall, M., 309 Fellous, M., 237 Feng, D.F., 447 Ferguson, C.E, 551

Ferrara, G.B., 803 Ferrier, P., 931 Fiddes, J.C., 657 Fiers, W., 587 Filippov, S.A., 611 Finger, L.R., 891 Finter, N.B., 571 Flake, A., 1073 Flandermeyer, R., 169 Forrest, S.M., 337 Foster, L., 75 Foster, W.B., 543 Foutch, L., 685 Francke, U., 855 Fransen, L., 587 Freedman, M., 1083 French Anderson, W., 1073 Friedlaender, J.S., 411 Friedmann, T., 1021 Frischauf, A.-M., 131 Fujita, A., 465 Fujita, T., 577 Fuscoe, J.C., 151, 159

G

Gatti, R., 785 Gazdar, A.E, 843 Georgiev, G.P., 611 Gerhard, D.S., 837 Giguere, V., 759 Gilboa, E., 1073 Gillespie, G.A., 123 Gilliam, T.C., 359 Gillio, A., 1073 Ginns, E.I., 1047 Gitschier, J., 365 Glaser, T., 837 Godfrey, M., 703 Goeddel, D.V., 597, 649 Goff, S.C., 177 Goldstein, J.L., 811 Gonzalez, EJ., 879 Gonzatti-Haces, M., 967 Goodfellow, P.J., 205 Goodfellow, EN., 205 Gorski, J., 67 Gray, A., 713 Gray, J.W., 141, 151, 159 Gray, P.W., 597 Green, C.L., 943 Green, P., 317 Green, S., 751 Greene, W.C., 731 Gregg, R.G., 1093 Grinfeld, E., 285 Groffen, J., 911 Groner, Y., 381 Gubler, U., 631 Guild, B.C., 1047 Gusella, J.E, 359

H

Hagen, E, 531 Haines, J., 359

1209

1210 AUTHOR INDEX

Halloran, S.L., 185 Haluska, EG., 891 Hamuro, J., 577 Hanauer, A., 195 Hancock, W.S., 551 Hansen, M.E, 829 Hardy, D., 75 Harris, P., 299 Harris, R., 551 Harrison, M.R., 1073 Hart, C., 531 Hatakeyama, M., 577 Hatton, K., 931 Hattori, M., 465 Hayashida, H., 429 Heilig, R., 195 Heisterkamp, N., 911 Henkel-Tigges, J., 1065 Herman, G.E., 1027 Hewick, R.M., 543, 685 Hewlett, B.S., 411 Hildebrand, C.E., 159 Hill, A.V.S., 489 Ho, Y.-S., 1033 Hobbs, H.H., 811 Hock, R.A., 1013 Hoeijmakers, J.H.J., 91 Hollenberg, S., 759 Honjo, T., 429, 739 Hood, L., 785 Hoover, M.L., 803 Horn, G., 263 Housman, D.E., 837 Hu, W.-S., 499 Hui, D.Y., 821 Huszar, D., 1083

I

Ichinose, A., 509 Igarashi, H., 959 Ihde, D.C., 843 Ikawa, S., 977 Innerarity, T.L., 821 Insley, M., 531 Ishida, N., 739 Iwamoto, A., 797

J

Jaiswal, A.K., 879 Johnson, B.E., 843 Johnson, M.S., 447 Johnsson, C., 221 Johnston, M.D., 571 Jolly, D.J., 1021 Jones, C., 837 Jong, S.-M., 773 Julier, C., 29

K

Kamen, R., 543, 685 Kan, Y.W., 169, 1033 Kanamori, H., 739 Kanda, N., 299 Kang, J., 299 Kantoff, P., 1073 Kaplan, L., 299 Karlsson, S., 1073 Karson, E., 1073 Kaufman, R.J., 543, 685 Kawasaki, E.S., 679 Kazazian, H.H., Jr., 371

Keck, R.G., 551 Keller, G., 1053 Kenwrick, S.J., 337 Keyt, B.A., 551 Kidd, J.R., 411 Kidd, K.K., 411 Kilian, P.L., 631 Kimura, N., 797 King, A.W., 337 Kinoshita, M., 739 Kisiel, W., 531 Klein, M., 785 Knowlton, R.G., 317 Koenig, M., 195 Kohn, D., 1073 Kohonen-Corish, M.R.J., 83 Kondo, S., 739 Korf, B., 299 Korobko, V.G., 611 Kr6nke, M., 731 Krust, A., 751 Kruyer, H., 309 Kuhara, S., 465 Kuhl, W., 1041 Kumar, A., 531 Kumar, V., 751 Kung, P., 785 Kunkel, L.M., 177, 349

L

Ladner, M.B., 679 Lai, E., 785 Lai, EH., 693 Lalande, M., 299 Lalazar, A., 821 Lalouel, J.-M., 29, 39 Lander, E., 49 Larson, R.A., 899 Lathrop, M., 29, 39 Latt, S.A., 299 Lau, Y.-F.C., 169 Lavenir, I.J.D., 337 Law, H.Y., 309 Lawn, R.M., 365 Lawrance, S.K., 123 Leary, A.C., 685 Lebacq-Verheyden, A.-M.,

843 Le Beau, M.M., 899 Lebo, R.V., 169 Ledley, ED., 395 Lee, B.S.M., 75 Legouy, E., 931 Lehrach, H., 131 Lehrman, M.A., 811 Lemons, R.S., 899 Lench, N., 309 Leonard, W.J., 731 Leppert, M., 29 Lerman, L.S., 285 Leroux-Roels, G., 587 Leroy, P., 237 Leung, D.W., 597 Levanon, D., 381 Levilliers, J., 221 Levy-Wilson, B., 821 Lewis, W.G., 571 Lewis, W.H., 837 Leytus, S.P., 509 Lijnen, H.R., 563 Lin, E-K., 693 Lindquist, P.B., 649

Littman, D.R., 703 Lomedico, ET., 631 Long, G.L., 525 Long, L.K., 983 Lucas, J., 141

M

MacDonal, M.E., 359 Mach, B., 67 MacLaughlin, D.T., 641 Maddon, D.E., 703 Maddon, P.J., 703 Magenis, E., 237 Magli, C., 1083 Mahley, R.A., 821 Mak, T.W., 797 Mandel, J.L., 195 Maniatis, T., 275 Mariottini, P., 103 Marks, J., 499 Marks, J., 803 Martin, B.M., 1047 Martin, D.W. Jr., 1059 Martin-Zanca, D., 983 Marvit, J., 395 Matsuda, E, 429 Matsui, H., 577 Matsunami, N., 739 McClelland, A., 725 McClure, M.A., 447 McDevitt, H.O., 75 McDougal, J.S., 703 McGlade, S.A., 337 McIvor, R.S., 1059 McKusick, V.A., 15, 121 McLachlin, J., 1073 Mengle-Gaw, L., 923 Mergia, A., 657 Metaxotou, C., 185" Mett, V.A., 611 Metzger, M., 685 Michiels, E, 131 Miller, A.D., 1013 Minamoto, S., 577 Minna, J.D., 843 Miskimins, W.K., 725 Mitra, G., 983 Miyata, T., 429 Monaco, A.P., 177, 349 Moores, J.C., 1021 Morgan, D.O., 773 Mori, H., 577 Motulsky, A.G., 403 Moyzis, R.K., 159 M~iller, U., 299 Mulligan, R.C., 1047 Mullis, K., 263 Mulshine, J., 843 Murray, G.J., 1047 Murray, M., 531 Murtha, P., 543 Myers, R.M., 275

N

Nakamura, Y., 29 Nakatsu, Y., 1001 Nau, M.M., 843 Nebert, D.W., 879 Nedospasov, S.A., 611 Nedwin, G.E., 597 Neer, A., 381 Nelson, D.L., 1065

Newburger, EE., 177 Nienhuis, A., 1073 Ninfa, E.G., 641 Nisen, P., 931 Nomoto, S., 1001 Norton, G.P., 1033 Nowak, N.J., 867

O

Oberl6, I., 195 O'Brien, W.E., 1027 O'Connell, P., 29 O'Hara, P., 531 Ohashi, E, 797 Oh-uchida, M., 1001 Oie, H.K., 843 O'Reilly, R., 1073 Orkin, S.H., 177 Oroszlan, S., 967 Ovchinnikov, Y.A., 611

P

P~i~ibo, S., 441 Page, D.C., 229 Palese, P., 1033 Palladino, M.A., 597 Palmer, T.D., 1013 Park, M., 967 Parker, P.J., 713 Patterson, M.N., 337 Patton, J.S., 597 Paulsen, K., 337 Paulson, K.E., 473 Pearson, EL., 353 Pech, M.W., 959 Pennica, D., 597 Perez-Stable, C., 499 Perlman, J., 159 Peters, D., 141 Petit, C., 221 Pettenati, M.J., 899 Petz, L.D., 257 Phillips, D.G., 371 Phillips, R.A., 1083 Pickering, L., 785 Pinkel, D., 141, 151 Pittman, D., 543 Pohl, T., 131 Poustka, A., 131 Pratt, D.J., 641 Pritchard, C., 205 Pym, B., 205

Q

Qin, S., 867

R

Rabbitts, P.H., 923 Rabbitts, T.H., 923 Ragan, C.I., 103 Rall, S.C., Jr., 821 Ralph, P., 679 Rao, C.D., 959 Raskin, P., 803 Ray, EN., 345 Reid, M.A., 83 Reis, M.D., 797 Remaut, E., 587 Respess, J.D., 1021 Riedel, H., 713

A U T H O R INDEX 1211

Rigas, B., 123 Robbins, K.C., 959 Roberts, M.P., 725 Robson, I., 1083 Rollini, E, 67 Rose, E., 299 Rosenfeld, M.G., 759 Rosenstock, J., 803 Rosenthal, A., 649 Rossant, J., 1083 Roth, R.A., 773 Rouyer, E, 221 Rowley, J.D., 899 Royer-Pokora, B., 177 Ruddle, EH., 725 Russell, D.W., 811 Rutter, W.J., 773

S

Sabe, H., 739 Sadler, J.E., 515 Saiki, R., 263 Saito, Y., 739 Sakai, K., 299 Sakaki, Y., 465 Sassone-Corsi, P., 949 Sato, T., 577 Sausville, E.A., 843 Sawada, I., 471 Scambler, P., 309 Scharf, S., 263 Schlessinger, J., 713 Schmid, C.W., 471,473 Schumm, J.W., 317 Seboun, E., 237 Seeburg, P.H., 669 Seifter, E., 843 Sekiguchi, M., 1001 Semba, K., 977 Serjeantson, S.W., 83 Shakhov, A.N., 611 Shaw, G., 685 Shaw, J.-P., 499 Shelton-Inloes, B.B., 515 Shen, C., 499 Shen, C.-K.J., 499 Shepard, H.M., 597 Sherr, C.J., 899 Shibuya, H., 577 Shiloh, Y., 299 Shimizu, A., 739 Shimizu, K., 1001 Shingarova, L.N., 611

Showe, L.C., 891 Shows, T.B., 867 Silva, A., 29 Silverstein, K., 285 Simmler, M.-C., 221 Singer, M.E, 457 Siniscalco, M., 191 Siu, G., 785 Skowronski, J., 457 Slaugenhaupt, S.A., 185 Smith, B.A., 213 Smith, C.L., 115, 123 Smith, T.J., 337 Smithies, O., 1093 Sorace, J.M., 515 Sorge, J., 1041 Spector, D.L., 943 Speer, A., 337 Spellman, M.W., 551 Spolski, R., 797 Srivastava, R., 123 Stam, K., 911 Stanier, P., 309 Stastny, P., 803 Stebbing, N., 693 Steinbrink, D.R., 685 Stern, A.S., 631 Stoneking, M., 433 Strauss E., 785 Strickland, T., 693 Stroh, H., 299 Strominger, J.L., 63 Stump, D.C., 563 Siidhof, T.C., 811 Suffys, P., 587 Sugarman, B.J., 597 Sullivan, N.F., 943 Suzuki, N., 739

T

Takenaka, O., 465 Taniguchi, T., 577 Tanzi, R.E., 359 Tavernier, J., 587 Taylor, A.M., 923 Taylor, J.M., 821 Tesfaye, A., 931 Testa, J.R., 967 Thomas, E.D., 1009 Thomas, K.R., 1101 Thompson, M.W., 345 Titani, K., 515 Toole, J.J., 543

Tosi, R., 803 Toyonaga, B., 797 Toyoshima, K., 977 Trask, B., 141, 151 Tsui, L.-C., 325 Tsuji, S., 1047 Tsujimoto, Y., 891 Tuddenham, E.G.D., 365 Tumolo, A., 657 Turetskaya, R.L., 611

U

Ucla, C., 67 Ueda, S., 429 Ullrich, A., 713, 855

u

Van Beveren, C., 949 van Dekken, H., 151 van den Engh, G., 141, 151 Van der Heyden, J., 587 Van Dilla, M.A., 141, 159 van Duin, M., 91 van Ommen, G.J.B., 353 Van Roy, E, 587 Vande Woude, G.F., 967 Vehar, G.A., 365, 551 Vergnaud, G., 221 Verma, I.M., 949 Vinocour, M., 843

W

Wager-Smith, K., 1065 Wagner, E.E, 1053 Wainwright, B., 309 Wallace, M., 359 Wallace, R.B., 257 Walter, P., 751 Wang, E.A., 685 Wang, J., 543 Wang, L.-H., 773 Warren, A.C., 185 Warren, M.K., 679 Wasley, L.C., 543 Watanabe, Y., 429 Waterfield, M.D., 713 Watson, E., 309 Watson, E., 693 Watt, R.A., 943 Weinberger, C., 759 Weisgraber, K.H., 821

Weiss, R.A., 703 Weissenbach, J., 221 Weissman, S.M., 123 West, C., 1041 Westbrook, C.A., 899 Westerveld, A., 91 Wexler, N.S., 359 Whang, J.L., 657 Wharton, R., 299 White, R., 29, 39 White, T.J., 679 Wigler, M., 993 Willard, C., 473 Willard, H.F., 325 Williams, S.R., 1059 Williamson, R., 309 Wilson, A.C., 433 Wilson, L., 337 Wion, K.L., 365 Witek-Giannetti, J.S., 685 Wolff, R., 29 Wong, C., 185, 371 Wong, G.H.W., 597 Woo, S.L.C., 395 Wood, P.A., 1027 Wood, W.I., 365 Woodbury, R., 531 Woodward, S., 29 Worrall, C., 309 Worton, R.G., 345 Wyman, A., 299

u

Yam, P.Y., 257 Yamada, G., 577 Yamamoto, T., 811 Yamamoto, T., 977 Yancopoulos, G., 931 Yang-Feng, T.L., 855 Yarden, Y., 713 Yasui, A., 91 Yee, J.-K., 1021 Yoshioka, K., 465 Young, D., 993 Youssoufian, H., 371

Z

Zanjani, E.D., 1073 Zehetner, G., 131 Zengerling, S., 325 Zimmerman, K., 931 Zwiebel, J., 1073

Subject Index

c~-Galactosidase A. See Galactosidase A

a-Globin. See Globin a-Thalassemia. See Thalassemia cq-Antiplasmin. See Antiplasmin a~-Antitrypsin deficiency. See Anti-

trypsin deficiency 2-Acetylaminofluorene, probe modifi-

cation, 152 Acetylation polymorphisms, 882 N-Acetyltransferase, acetylation poly-

morphism, 882 Achiropody, Brazilian type, 57 Acquired immune deficiency syn-

drome. See AIDS Acromegaly, 669 Acute nonlymphocytic leukemia. See

ANLL ADA (adenosine deaminase) defi-

ciency, 1059, 1065 ADA retroviruses, 1068-1069. See also

Gene transfer, nonhuman pri- mates

Adenosine deaminase. See ADA Adipocytes

cachectin effects, 625 catabolic effects of cytokines, 605,

606 Admixture mapping methods, 53-54 ADP-ribosylation consensus sequence,

97-99 AEV (avian erythroblastosis virus)

homology with steroid receptors, 759

oncogenic potential of, 769 African ape. See Hominoid evolution AHH (aryl hydrocarbon hydroxylase)

inducibility and lung cancer, 885

Ah locus, 883-885 Ah receptor, 884 AIDS (acquired immune deficiency

syndrome) viruses, 703-712 Albinism, genetic heterogeneity, 53 Allele-specific oligonucleotide probes,

263-264, 271-272 Alternative splicing, tissue-specific, 22 Alu-like sequences, 471,473 Alu sequences, 457

consensus sequence, 471 evolution, 471,472-473 gene correction, 501 a-globin gene structure, 500, 501 interaction with topoisomerase I,

501-502 LDL receptor, 813-814, 816 TNF-c~ and -/3 locus, 620, 621

Amber codon suppression. See Sup- pressor tRNA

Amphotropic murine retrovirus, 1014-1016, 1050-1051, 1087. See also

Gene transfer; Retroviral vec- tors

Amplification chromosomal, 299-308 of DNA, PCR, 263-272 and oncogene activation, 983. See

also specific oncogenes Anemia, 693, 699-700, 882, 900,

906-907 Aneuploidy detection, 156 Angiogenesis, 657

autocrine and paracrine role of TGF-a, 651

Aniridia, 873. See also WAGR syn- drome

ANLL, CSF-1 and FMS in pathogen- esis, 899-900, 906-907

Anthropoidea divergence, 422 Anti-cancer agents, 571-646

interferons, 571-575, 587 interleukin-l, 631-638 interleukin-2, 577-584, 587 MIS, 641-646 TNF-a and TNF-/3, 588-594,

597-608, 611-622 Anti-clotting factors

scu-PA, 563-568 t-PA, 509, 551-560

Anti-oncogenes, 940 c~2-Antiplasmin, 563, 565, 567 Anti-Tac. See Interleukin-2 receptor;

T-cell leukemia c~-Antitrypsin deficiency, 56 Antiviral activity

interferons, 571,603-604 TNF-u and TNF-/3, 602-604

Apo-B. See Apolipoprotein Apo-E. See Apolipoprotein Apolipoprotein. See also LDL recep-

tor A1, 404 A 1-CIII locus, linkage equilibrium,

406-407 B48, 826 B100, 826 B sites of synthesis, 826 B and E, receptor binding, 821-827 DNA variants, 404-405, 407 E binding to hepatic receptor, 821 E receptor-defective variants,

824-825 E sites of synthesis, 823-824 genes as chromosomal markers, 873,

875 RFLP alleles, 406 site-directed mutagenesis of E, 826

Apolipoprotein B,E(LDL) receptor structure, 821-823

radiation inactivation, 823 Apolipoproteins, hyperlipidemia, and

CHD, 11, 403-408 Apoprotein. See Apolipoprotein Argininosuccinate synthetase (AS).

See Citrullinemia Aryl hydrocarbon hydroxylase. See

AHH AS. See Argininosuccinate synthetase

Asialoglycoproteins plasma clearance, 691 receptor (hepatic-specific), 1031

ASO. See Allele-specific oligonucleo- tide

Ataxia telangiectasia DNA damage and repair, 91 gene rearrangements in T-CLL,

927 -929 genetic heterogeneity, 53

ATPase 8, 108 Australopithecus, 425 Autocrine growth factors and lung

cancer, 843-851 Autocrine hypothesis of tumor devel-

opment, 641,651-654. See also EGF, PDGF, GM-CSF, and TGF-a

Autoimmune diseases and HLA class II polymorphism, 72-73, 79-81. See also IDDM

Autophosphorylation effect on function of the insulin re-

ceptor, 776-778 insulin-stimulated, 715-716 sites in insulin receptor, 776 transforming proteins and growth

factor receptors, 773-774, 780-782

Avian erythroblastosis virus. See AEV

B

/3-Globin. See Globin /3-Thalassemia. See Thalassemia /32-Microglobulin. See Microglobulin Backcross, use in linkage studies,

39-41 Banding analysis, 144, 151, 154, 155.

See also Chromosome band- ing

B-cell malignancies, 875, 891-895. bcl-1 and bcl-2 loci, 892-894 translocations, 891-895

bcl-1 and bcl-2, 892-894, 897 Becker muscular dystrophy. See BMD Beckwith-Wiedemann syndrome

association with Wilms' tumor, 857, 873

gene duplications and rearrange- ments, 857, 873

IGF-II and pathogenesis, 857 mapping to chromosome 11, 868,

872 Biotin-dUTP, probe modification, 152 Biotinylated nucleotide-tagged probes,

128 Bladder cancer

acetylation polymorphism, 882 and urogenital tumors of childhood,

874

1213

1214 S U B J E C T I N D E X

Blood-clotting cascade, vitamin-K-de- pendent proteases, 525, 531

Blood-clotting factors. See also Clot- ting factors.

structural features and homologies, 509-513

BMD (Becker muscular dystrophy). See also DMD

candidate region for DMD, 309 deletion detection, 349, 350 localization of mutation, 337-338 X-autosome translocation, 337-338,

345-348 Bombesin-like peptides. See GRP Bone-marrow stem cells. See Gene

transfer Bone-marrow transplant

aplastic anemia, 1009, 1010 Gaucher disease, 1047 genetic markers for engraftment,

258, 259, 318-319 leukemias, 1009-1010 severe combined immune deficiency,

1009, 1010, 1065 strategies, 1009-1010 thalassemia major, 1009-1010

Breakpoint cluster region (bcr), 911, 913-916

Bronchogenic carcinoma. See Lung cancer

Burkitt's lymphoma. See also c-myc chromosomal translocations, 855,

891, 892, 924, 925 flow karyotypes, 142, 144, 146 immunoglobulin gene rearrange-

ments, 895

C

c-abl CML, 8, 855, 911-920 gene localization, 912 homology with v-src and v-abl, 919

Cachectin, 590, 625-628 Cachexia, 625 Calcitonin, chromosome 11 marker,

868, 872 Calcium-binding sites in PKC family,

718-722 Calcium homeostasis, 23 Calmodulin, homology with PKC cal-

cium-binding domain, 718 Camptothecin, 501,502 Canavanine, 1028 Cancer. See also Oncogene; Proto-on-

cogene; specific types adult bladder carcinoma and child-

hood urogenital tumors, 874 chromosomal mapping of genes in-

volved in growth control, 855-864

cytochrome P450 gene superfamily, 11, 879-888

DNA repair deficiencies, 11 environmentally caused, 879, 886,

887 molecular genetics of human fami-

lial cancer, 829-834 predisposition, 33, 35, 56, 232,

829-888 tumor-associated gene rearrange-

ments, 891-929

Carrier detection. See specific syn- drome or disease

Catalase chromosome 11 short-arm marker,

868, 872-873 gene deletion in WAGR syndrome,

837 marker for Wilms' tumor region,

837 Catarrhini, primate taxonomic subdi-

vision, 419 Cathepsin D, chromosome 11 short-

arm marker, 868, 872 Cell lineage analysis, 1086. See also

Retroviral vectors Cell-surface receptors, AIDS virus,

703-712 Centre d'l~tude du Polymorphisme

Humain (CEPH), 30, 41 Centromeric index, 146-148 c-erbA

homology with steroid receptors, 766-767, 769-770

isolation and characterization of cDNA, 764-765

transcriptional activator protein, 759-770

c-erbB-1, EGF receptor gene, 977, 978 c-erbB-2

amplification in adenocarcinoma, 978, 979

characterization, 978 gene product structure, 979-981 glycosylation, 981-982 homology with neu, 981 locus localization and acute promye-

locytic leukemia, 979 relationship to EGF receptor,

977-982 tyrosine kinase domain, 981-982

Cercopithecoidea, 421 Ceruloplasmin, homology with Factor

VIII, 366, 543 c-fos. See also fos gene

characterization of gene product, 952-953

mRNA and interleukin-2, 583, 584 mRNA stability, 956 regulation of transcription, 954-955 transforming potential, 953-954

CGD (chronic granulomatous disease) and b-type cytochromes, 177, 182 cloning by linkage, 177-182 mapping of the gene locus, 177-178,

357 phagocyte NADPH-oxidase system,

177, 182 Xp21 transcripts, 178-182

Charcot-Marie-Tooth syndrome antithrombin III gene, 173 genetic heterogeneity, 53 linkage to Duffy blood-group locus,

173-174 search for markers, 169, 173-174

CHD. See Coronary heart disease Chiasma formation and trisomy 21,

185 Chimeric insulin/EGF receptor,

714-716 Chimeric phl/c-abl in CML, 911,

916-919 Chimerism in bone-marrow trans-

plants, 258, 259, 318-319 Chimpanzee and human origins. See

Evolution; Hominoid evolu- tion

Chloride transport, 325 Cholesterol metabolism. See LDL re-

ceptor Christmas disease. See Hemophilia B Chromomycin A3, use in flow cytome-

try, 141-149, 160, 169, 170 Chromosomal aberrations

detection in flow-sorted chromo- somes, 141-144, 169, 172, 299-301, 304

molecular probes, 299-305 Chromosomal translocations

B-cell malignancies, 894-895, 924, 925

immunoglobulin gene rearrange- ment, 894-895, 924, 925

T-cell receptor genes, 896 Chromosome 7, 319-322, 325-333 Chromosome 11

fragile site, 869 gene map, 837-840, 867-875 markers, 868, 872-873 rearrangements, 840, 869, 872,

874-875 regions involved in growth, 868-869,

873-875 Chromosome banding, 15-17. See also

Banding analysis; Genome analysis of sorted chromosomes, 161 gene mapping, 15-17 relationship to synteny, 20 Y chromosome anomalies, 230

Chromosome breakpoints cluster region on chromosome 22

and relationship to CML, 911,913-916

T-cell receptor, 895-896 Chromosome classification. See Flow

cytometry; Flow karyo- typing; Flow-sorted chromo- some libraries; Fluorescence hybridization

Chromosome deletion. See specific disease or syndrome

Chromosome distribution patterns, 46 Chromosome-enriched recombinant li-

braries, 159-166, 169, 173-174, 299

Chromosome isolation, 141, 160, 161. See also Flow cytometry; Flow-sorted chromosome li- braries

Chromosome jumping, 127-128, 131-133

Chromosome linkup, 135-138 Chromosome-mediated gene transfer

(CMGT), 206, 209-210, 313 Chromosome sorting, 141, 144-149,

160-161, 162-163, 169-170 Chromosome-specific probes, 151,

154-156 Chromosome staining for flow analy-

sis, 141, 152, 160, 161, 169, 170 Chromosome suspension preparation,

169 Chronic granulomatous disease. See

CGD Chronic lymphocytic leukemia. See

CLL Chronic myelocytic (myelogenous) leu-

kemia. See CML Ciliary dyskinesis factor, 310

S U B J E C T I N D E X 1215

Citrullinemia, 1027 amphotropic AS retrovirus,

1028-1029 A S locus, 1030-1031 citrulline incorporation, 1027,

1028-1029, 1031 gene therapy, 1027-1028 hepatocyte targeting, 1031

Clotting cascade, 525, 531 Clotting factors, 509-548. See also Gla

domain; Inhibitors; specific plasma proteins

C-kinase and c-erbB-2, 982 Classical hemophilia. See

Hemophilia A CLL (chronic lymphocytic leukemia)

bcl-1,892 gene rearrangements, 894, 925-929 possible oncogene, 875

Cloning megabase DNA regions, 127-129

CMGT. See Chromosome-mediated gene transfer

CML (chronic myelocytic [myeloge- nous] leukemia). See also c- abl; Philadelphia chromo- some

bcr locus, 913-916 Philadelphia chromosome-negative,

914 and t-PA, 862 transforming events, 911-920

c-myb, 848-849 c-myc, 8, 931, 943. See also myc family

amplification and expression in SCLC, 846-847

colocalization with snRNPs, 943 -946

translocation in Burkitt's lym- phoma, 891, 892, 924

translocation and T-cell receptor a- chain, 799, 895-896

Coagulation factor genes. See Clotting factors

Coding ratio, 6-7 Coding sequences, compositional con-

straints, 481-484 Codon usage, 484-485, 526, 527 Coelic disease and HLA class II poly-

morphism, 81 Cold-blooded to warm-blooded verte-

brate transition, 484, 485 Collagen-binding site of yon Wille-

brand factor, 515, 519-521 Colon carcinoma. See also Gardner's

syndrome trk oncogene, 855, 983-991

Colony-stimulating factors, 899. See also CSF-1, GM-CSF

Color blindness, 9, 15 Comparative morphology, use in inter-

pretation of phylogeny, 419, 421-422

Complement activation, 509-513 Complement components

3 and cystic fibrosis, 309 association in HLA gene cluster, 2 B, 519 C2, 519 C4 linkage disequilibrium, 83 Clr homology to GP-I and EGF, 513

Complex multifactorial traits, 9-11 Compositional constraints in human

genome, 479-486

Congenital chloride diarrhea, founder effect, 59

Consanguinity in genetic disorders, 57-58

Cornea planta congenita recessiva, founder effect, 59

Coronary heart disease (CHD) DNA variants at apolipoprotein

loci, 404-405 effects of apolipoproteins, 11 molecular biology, 403-408

Coronary occlusion, and thrombo- lysis. See scu-PA; t-PA

Cosmid cloning, use in genetic map- ping, 9, 30, 31, 135-138

Cosmid linkup, 135-138 "Cot analysis," 16 Cotransfection and tumorigenicity as-

say, 993 CpG dinucleotide

compositional constraints in the ge- nome, 481-483

methylation and jumping fragments, 126

methylation and PFGE analysis, 116 mutations, 257, 375-377

c-raf-1, 1001-1007 expression in SCLC, 849

Crossing-over. See also Recombination between X and Y chromosomes,

249-251 effect of sex on frequency, 41 flanking-marker RFLP test,

322-323 interference, 42-44 pseudoautosomal region, 221,223,

224 relationship of genetic and physical

maps, 39, 41 CSF-1 (colony-stimulating factor-l)

biological properties, 679-681,682 localization, 899-907 receptor, 713-714 relation of receptor to FMS, 899 role in myelodysplastic syndromes,

907 c-sis/PDGF-2 gene, 959-965. See also

PDGF CuZnSOD. See Superoxide dismutase Cystic fibrosis (CF), 57, 309, 325

absence of linkage disequilibrium, 311,313

antenatal diagnosis inadequacies, 313

candidate genes and regions, 309-310

carrier detection, 313 cDNA libraries, 310 chloride transport, 325 chromosome-mediated gene trans-

fer, 313 cosmid clone use in gene mapping,

313 genetic diagnosis, 332-333 genetic heterogeneity, 333 linkage disequilibrium, 332, 333 linkage relationships, 177, 311-314,

325-333 linkage relationships and RFLP

analysis, 49, 319-322 paraoxonase locus, 311,325, 327-329 prenatal diagnosis, 35, 37, 311 presymptomatic diagnostic testing

and RFLP analysis, 317,

322-323 relationship to met. See met

Cytochrome, b-type, X-linked CGD, 177, 182

Cytochrome c oxidase, 103, 105, 108 Cytochrome P450

Ah locus, 883-885 debrisoquine metabolism, 11, 883 effect of immunosuppressants on

activity, 882 enzyme activity, 879-880 gene expression and cancer, 882,

883-885 gene regulation, 881, 885-887 homology between mouse and hu-

man genes, 885-886, 888 metabolism of environmental pollu-

tants, 879 pharmacogenetic polymorphisms,

879 in prokaryotes and eukaryotes,

879-880 superfamily evolution, 880-881

Cytokines, 597-608 Cytosine methylation of Factor IX,

528-529

D

DAPI (4',6-diamidino-2-phenylindole), DNA-specific dye, 141, 160

DAPI-Netropsin staining of sorted chromosomes, 161

Debrisoquine metabolism (polymor- phism), association with can- cer, 11,883

Deficiency alleles Factor VIII:C, 371, 374-378 ~-globin, 371-374

Deletion. See specific diseases and loci Deletion mapping, 340

chromosome 11,869-875 male-determining function of the

human Y chromosome, 229-234

T-cell receptor V~ segment, 790-791 Deletion mutation, correction of DNA

through gene targeting (gene conversion), 1103-1106, 1108-1109

Deletion-related disease, 191-193. See also specific disease

Denaturing gradient gel electrophore- sis, 275-279, 281-283, 285-298

Diabetes mellitus, insulin-dependent. See IDDM

Diagnosis, genetic. See Genetic diag- nosis.

Diagnostic applications of RFLP probes, 317-324, 368-369

Dihydrofolate reductase gene promoter sequence homology to

transferrin receptor pro- moter, 726, 728

selectable marker in retroviral vec- tors, 1014

Dioxin-inducible enhancer, cyto- chrome P450, 885-886, 887

DIPI, DNA-specific dye for flow anal- ysis, 169, 170

1216 S U B J E C T I N D E X

Disease. See also Genetic disease application of mapping informa-

tion, 24 founder effect, 59 genetic heterogeneity, 9, 53 incomplete penetrance, 54 molecular probes of chromosome

aberrations, 299-305 Disease associations with HLA sys-

tem. See HLA. Disease, autoimmune, and HLA class

II polymorphisms, 72-73, 79-81

Disease gene isolation, "genome walk- ing" strategies, 199-202

Disease gene mapping, 177 RFLP linkage mapping, 16, 49-61

Disease and recombination, 191-193 Disease susceptibility

genetic predisposition, 56, 403-404 and HLA class II polymorphism,

79-81. See also Linkage dis- equilibrium.

Diseases with unknown primary defect cystic fibrosis, 309-314 genetic mapping of the X chromo-

some, 199 polmorphic markers, 173

Diseases with X-linked inheritance, 195-198, 337-341. See also in- dividual syndromes

Disequilibrium, linkage. See Linkage disequilibrium

Disequilibrium mapping, 58-59 Disequilibrium statistic ,~, 84 Divergence, evolutionary, in primates,

419-428 DMD (Duchenne muscular dystro-

phy), 177, 353 candidate gene sequences involved

in etiology, 309, 338-339 carrier detection, 338, 353-354 cloning of junction of X;21 translo-

cation, 345-346 deletions, 339-340, 349-350, 353 DNA probe analysis in diagnosis,

353-355 expressed sequences of X chromo-

some, 338-339 genetic heterogeneity, 339-340 identification of DNA regions im-

portant for phenotype expression, 350

linkage analysis, 337-339, 349-351 locus, meiotic recombination, 338,

348, 353-354, 355 molecular genetics, 349-351 nonrandom inactivation of maternal

gene on X chromosome, 346 nucleotide sequence conservation,

350 origin of mutations, 355, 356 paternal inheritance of translocation

chromosomes, 346 PFGE in mapping and molecular

analysis, 340, 355 prenatal diagnosis, 353-355 reciprocal nature of translocation,

346 region, megabase map, 355, 357 segregation of RFLP markers, 338,

347, 349 unequal crossing-over contributes to

mutation, 355

X-autosome translocations, 337-338, 345-348, 353

DNA amplication. See Amplication DNA from ancient human remains,

441-445 DNA-based detection of chromosomal

aberrations, 299-305 DNA clocks, relative evolutionary

time scale, 421-425. See also Molecular clocks

DNA content, chromosome descriptor in slit-scan flow cytometry, 146-148

DNA damage and repair, 91 DNA markers and human genetic vari-

ation, 411-416 DNA methylation. See also CpG

dinucleotide Factor IX, 528-529

DNA polymorphism, genetic varia- tion. See Genetic variation; Polymorphism; RFLP

DNA repair genes, 91-99. See also ERCC-1

DNA sequence variants, analysis of, 285

denaturing gradient gel electropho- resis, 275-279, 281-283, 285-293

oligonucleotide hybridization, 257-260

ribonuclease cleavage, 279-283 DNA stains. See Chromosome staining

for flow analysis Double-minute bodies, amplified se-

quences in neuroblastoma tis- sue, 302-303

Down's syndrome nondisjunction in trisomy 21,

185-189, 381 superoxide dismutase overproduc-

tion in etiology, 381-391 Drug-resistance genes as selectable

markers in retroviral vectors. See Gene therapy; Retroviral vectors

Drugs made off human genes, 509-570. See also Anti-cancer agents; Anti-clotting factors; Growth factors

Dryopithecus, 419 Duchenne muscular dystrophy. See

DMD Duffy blood-group locus

chromosome 1 assignment, 15 linkage to Charcot-Marie-Tooth

syndrome, 173-174 Dyes, DNA-specific fluorescent. See

Chromosome staining Dysgerminoma, predisposition, 232

E

E7 antibody, chromosome 11 short- arm marker, 868, 872, 874

12E7 antigen expression, 205, 210, 250 E. coli DNA repair enzyme, homology

with ERCC-1, 96, 97, 454 E. coli DNA repair systems, 91 E. coli recA protein (RecA), in cloning

megabase regions of DNA, 128

EGF (epidermal growth factor) noncatalytic chain domains of

serine proteases, 509 probes and mapping of gene, 855,

856 precursor homology with LDL re-

ceptor domain, 812 EGF receptor gene (EGFR)

autocrine hypothesis of transforma- tion, 651-654

autophosphorylation sites, 773-774 c-erbB-l, 977 probes and mapping, 855, 860 relationship to c-erbB-2, 977,

981-982 TGF-c~ interaction, 649, 651,654 tyrosine kinase receptor type 1,713,

714-716 EGF receptor variant (HER2)

receptor probes and mapping, 855, 860-861

tyrosine kinase receptor type 1, 713, 714

Ehlers-Danlos syndrome type VII, ge- netic heterogeneity, 19

Electrophoresis, denaturing gradient gel. See Denaturing gradient gel electrophoresis

Electroporation, gene targeting, 1096 Elliptocytosis, genetic heterogeneity,

9, 53 ELOD. See Lod score Embryonal tumors, N-myc expression,

931,932, 936-937, 940 Emphysema, genetic predisposition,

56 Encephalopathy, alcohol-induced,

penetrance of trait, 54 Endosome internalization of T4-AIDS

virus complex, 707-709 Endothelial cell growth factors, possi-

ble signal for angiogenesis, 657-666

Endothelial cell mitogens, heparin- binding, 657-666

Endotoxin-induced cachectin release, 625-626

Endotoxin-induced systemic LPL defi- ciency and hyperglyceride- mia, cachexia, 625

Endotoxin toxicity (shock), 627 Enhancer binding proteins, 759-770 Enzymatic amplification of DNA,

PCR, 263-272 Enzymatic digestion, PFGE analysis,

116-118, 124, 126-127 Enzymes, functional anatomy of the

human genome, 21 Epidermal growth factor. See EGF Epileptic, subphenotype, 61 EPO. See Erythropoietin Epstein-Barr virus transformation

procedure, 60 erbA

multiple genes, 766, 770 polypeptide homology

steroid receptors, 766-767, 769-770

TFIIIA, 768, 769 proto-oncogene products, superfam-

ily of enhancer binding pro- teins, 756, 759-770

S U B J E C T I N D E X 1217

sequence comparisons, human and viral, 764-766

ERCC-1, 92-99, 454 Erythropoietin (EPO), 693-701 Escherichia coli. See E. coli Estrogen receptor, 751-757. See also

Steroid receptors Estrogen-responsive element of Xeno-

pus vitellogenin gene, 757 ETS1 proto-oncogene, chromosome 11

long-arm marker, 868, 873 Evolution. See also Alu sequence; Ge-

netic variation; a-Globin; Hominoid evolution; Immu- noglobulin

compositional constraints on human genome, 479-486

fossil evidence, 419-427 of genetic variation, 411-416 of human protein sequences,

447-454 mtDNA, 433-438 primates

c~-globin genes, 471-473, 499-504 01-globin gene, 505-507 immunoglobulin genes, 429-432

repetitive DNA sequences, 457-463, 465-468, 471-477

study of ancient human remains, 441-445

Evolutionary distance, 447, 448 Excision-repair system, 91-99 Exon shuffling

DNA-repair enzymes, 454 evolution of protein sequences, 450,

451,453 evolutionary rationale for introns,

20 LDL receptor, 813, 814 T4 and T8 evolution, 705

Extrinsic pathway in clotting cascade, 531

F

Facioscapulohumeral muscular dystro- phy, localization of, 33, 37

Factor V, 509, 543-544, 548 Factor VII. See also Factor IX/VII fu-

sion protein activated form (VIIa) to bypass in-

trinsic pathway, 532 activation, 531 alternative splicing, 534 base composition