| CLASSIC
Eric Lander and David Botstein on Mapping Quantitative Traits Gary A. Churchill1 The Jackson Laboratory, Bar Harbor, Maine 04609
ORIGINAL CITATION Mapping Mendelian Factors Underlying Quantitative Traits Using RFLP Linkage Maps. Eric S. Lander and David Botstein GENETICS January 1, 1989 121: 185–199
T
he rediscovery of Mendel’s work in the early 20th century sparked heated debate about the inheritance of continuously variable “size” traits (e.g., East 1916). But, although evidence accumulated in support of Mendelian models of quantitative trait inheritance, for most of the century it was rare for geneticists to be able to link such traits to specific Mendelian factors. The principles of mapping quantitative traits to qualitative characters had been well understood since Sax (1923) established the linkage of seed size to pigmentation in beans. What was missing was a systematic method to identify the specific factors underlying quantitative traits, to estimate their effects, and to characterize their interactions. The foundation for change began with a proposal to develop genome-wide maps of restriction fragment length polymorphism (RFLP) markers in humans (Botstein et al. 1980). In principle, RFLP markers fell close enough together that the whole genome could be efficiently scanned for linkage to a trait of interest. But it was the landmark article of Lander and Botstein (1989) that brought together the power of model organism crosses with genome-wide RFLP maps and provided a systematic strategy for mapping the long sought factors or quantitative trait loci (QTL). The key innovation—known as interval mapping—is a statistical algorithm to use all of the information available in the genome-wide markers. This increased the power and precision of mapping in comparison to older methods that evaluated linkage one marker at a time. By bridging the gaps between markers, the Copyright © 2016 by the Genetics Society of America doi: 10.1534/genetics.116.189803 Image of Eric Lander (left) and David Botstein (right) courtesy of Cold Spring Harbor Laboratory Archives. 1Address for correspondence: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. E-mail: [email protected]
log-likelihood profiles obtained from interval mapping provided the first genome-wide view of the QTL landscape. Lander and Botstein (1989) is rich with ideas and open questions that fueled methodological research, including the problem of multiple testing in genome-wide searches (Churchill and Doerge 1994). Lander and Botstein (1989) also addressed practical questions of study design that inspired and empowered hundreds of applications of their method in agricultural, biomedical, and basic research in the decades that followed. Researchers were soon faced with new questions and challenges, however. QTL were numerous and the effort of isolating the causal genes and variants often proved to be daunting. Studies of blood pressure in the laboratory rat, for example, identified QTL on almost every chromosome (Rapp 2000). QTL could encompass multiple tightly linked variants; they were often dependent on genetic background or environmental contexts; their effects could be small or large, pleiotropic, additive, or epistatic. In an early and innovative application, Damerval and colleagues (1994) applied QTL mapping to the quantitative expression of proteins (Damerval et al. 1994). QTL mapping of molecular phenotypes has since revealed elaborate networks of genetic regulation. Application of Lander and Botstein’s method for isolating Mendelian factors has revealed the true magnitude of quantitative genetic complexity, confirming an expectation set forth a century ago by the first geneticists.
Literature Cited Botstein, D., R. L. White, M. Skolnick, and R. W. Davis, 1980 Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am. J. Hum. Genet. 32: 314–331.
Genetics, Vol. 203, 1–3 May 2016
1
Churchill, G. A., and R. W. Doerge, 1994 Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971. Damerval, C., A. Maurice, J. M. Josse, and D. de Vienne, 1994 Quantitative trait loci underlying gene product variation: a novel perspective for analyzing regulation of genome expression. Genetics 137: 289–301. East, E. M., 1916 Studies on size inheritance in Nicotiana. Genetics 1: 164–176. Rapp, J. P., 2000 Genetic analysis of inherited hypertension in the rat. Physiol. Rev. 80(1): 135–172. Sax, K., 1923 The association of size differences with seed-coat pattern and pigmentation in Phaseolus vulgaris. Genetics 8: 552–560.
Further Reading in GENETICS Dilda, C. L., and T. F. C. Mackay, 2002 The genetic architecture of Drosophila sensory bristle number. Genetics 162: 1655–1674. Hill, W. G., and T. F. C. Mackay, 2004 D. S. Falconer and introduction to quantitative genetics. Genetics 167: 1529–1536. Jansen, R. C., 1996 A general Monte Carlo method for mapping multiple quantitative trait loci. Genetics 142: 305–311. Sen, S., and G. A. Churchill, 2001 A statistical framework for quantitative trait mapping. Genetics 159: 371–387. Studer, A. J., and J. F. Doebley, 2011 Do large effect QTL fractionate? A case study at the maize domestication QTL teosinte branched1. Genetics 188: 673–681. Weiss, K. M., 2008 Tilting at quixotic trait loci (QTL): an evolutionary perspective on genetic causation. Genetics 179: 1741– 1756. Zeng, Z. B., 1994 Precision mapping of quantitative trait loci. Genetics 136: 1457–1468.
Other GENETICS Articles by E. S. Lander and D. Botstein Adams, A. E., and D. Botstein, 1989 Dominant suppressors of yeast actin mutations that are reciprocally suppressed. Genetics 121: 675–683. Botstein, D., 1992 1992 Genetics Society of America Medal: Maynard V. Olson. Genetics 131: S11–S12. Botstein, D., 2004 Ira Herskowitz: 1946–2003. Genetics 166: 653–660. Botstein, D., and G. R. Fink, 2011 Yeast: an experimental organism for 21st century biology. Genetics 189: 695–704. Brandriss, M. C., L. Soll, and D. Botstein, 1975 Recessive lethal amber suppressors in yeast. Genetics 79: 551–560. Carlson, M., B. C. Osmond, and D. Botstein, 1981a Mutants of yeast defective in sucrose utilization. Genetics 98: 25–40. Carlson, M., B. C. Osmond, and D. Botstein, 1981b Genetic evidence for a silent SUC gene in yeast. Genetics 98: 41–54. Carlson, M., B. C. Osmond, L. Neigeborn, and D. Botstein, 1984 A suppressor of SNF1 mutations causes constitutive high-level invertase synthesis in yeast. Genetics 107: 19–32. Caudy, A. A., Y. Guan, Y. Jia, C. Hansen, C. DeSevo et al., 2013 A new system for comparative functional genomics of Saccharomyces yeasts. Genetics 195: 275–287. Chan, C. S., and D. Botstein, 1993 Isolation and characterization of chromosome-gain and increase-in-ploidy mutants in yeast. Genetics 135: 677–691. Chan, R. K., and D. Botstein, 1976 Specialized transduction by bacteriophage P22 in Salmonella typhimurium: genetic and physical structure of the transducing genomes and the prophage attachment site. Genetics 83: 433–458.
2
G. A. Churchill
Dietrich, W., H. Katz, S. E. Lincoln, H. S. Shin, J. Friedman et al., 1992 A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131: 423–447. Falco, S. C., and D. Botstein, 1983 A rapid chromosome-mapping method for cloned fragments of yeast DNA. Genetics 105: 857– 872. Falco, S. C., M. Rose, and D. Botstein, 1983 Homologous recombination between episomal plasmids and chromosomes in yeast. Genetics 105: 843–856. Gould, K. A., W. F. Dietrich, N. Borenstein, E. S. Lander, and W. F. Dove, 1996a Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics 144: 1769–1776. Gould, K. A., C. Luongo, A. R. Moser, M. K. McNeley, N. Borenstein et al., 1996b Genetic evaluation of candidate genes for the Mom1 modifier of intestinal neoplasia in mice. Genetics 144: 1777–1785. Gresham, D., V. M. Boer, A. Caudy, N. Ziv, N. J. Brandt et al., 2011 System-level analysis of genes and functions affecting survival during nutrient starvation in Saccharomyces cerevisiae. Genetics 187: 299–317. Heck, J. A., D. Gresham, D. Botstein, and E. Alani, 2006 Accumulation of recessive lethal mutations in Saccharomyces cerevisiae mlh1 mismatch repair mutants is not associated with gross chromosomal rearrangements. Genetics 174: 519– 523. Huisman, O., W. Raymond, K. U. Froehlich, P. Errada, N. Kleckner et al., 1987 A Tn10-lacZ-kanR-URA3 gene fusion transposon for insertion mutagenesis and fusion analysis of yeast and bacterial genes. Genetics 116: 191–199. Hulbert, S. H., T. W. Ilott, E. J. Legg, S. E. Lincoln, E. S. Lander et al., 1988 Genetic analysis of the fungus, Bremia lactucae, using restriction fragment length polymorphisms. Genetics 120: 947–958. Kleckner, N., D. F. Barker, D. G. Ross, and D. Botstein, 1978 Properties of the translocatable tetracycline-resistance element Tn10 in Escherichia coli and bacteriophage lambda. Genetics 90: 427–461. Kleckner, N., D. A. Steele, K. Reichardt, and D. Botstein, 1979 Specificity of insertion by the translocatable tetracycline-resistance element Tn10. Genetics 92: 1023–1040. Kruglyak, L., and E. S. Lander, 1995 A nonparametric approach for mapping quantitative trait loci. Genetics 139: 1421–1428. Kunes, S., H. Ma, K. Overbye, M. S. Fox, and D. Botstein, 1987 Fine structure recombinational analysis of cloned genes using yeast transformation. Genetics 115: 73–81. Kunes, S., D. Botstein, and M. S. Fox, 1990 Synapsis-mediated fusion of free DNA ends forms inverted dimer plasmids in yeast. Genetics 124: 67–80. Lang, G. I., D. Botstein, and M. M. Desai, 2011 Genetic variation and the fate of beneficial mutations in asexual populations. Genetics 188: 647–661. Maurer, R., B. C. Osmond, and D. Botstein, 1984a Genetic analysis of DNA replication in bacteria: dnaB mutations that suppress dnaC mutations and dnaQ mutations that suppress dnaE mutations in Salmonella typhimurium. Genetics 108: 25–38. Maurer, R., B. C. Osmond, E. Shekhtman, A. Wong, and D. Botstein, 1984b Functional interchangeability of DNA replication genes in Salmonella typhimurium and Escherichia coli demonstrated by a general complementation procedure. Genetics 108: 1–23. Moir, D., and D. Botstein, 1982 Determination of the order of gene function in the yeast nuclear division pathway using cs and ts mutants. Genetics 100: 565–577. Moir, D., S. E. Stewart, B. C. Osmond, and D. Botstein, 1982 Coldsensitive cell-division-cycle mutants of yeast: isolation, properties, and pseudoreversion studies. Genetics 100: 547–563.
Novick, P., B. C. Osmond, and D. Botstein, 1989 Suppressors of yeast actin mutations. Genetics 121: 659–674. Ohya, Y., and D. Botstein, 1994 Structure-based systematic isolation of conditional-lethal mutations in the single yeast calmodulin gene. Genetics 138: 1041–1054. Paterson, A. H., S. Damon, J. D. Hewitt, D. Zamir, H. D. Rabinowitch et al., 1991 Mendelian factors underlying quantitative traits in tomato: comparison across species, generations, and environments. Genetics 127: 181–197. Poirier, C., Y. Qin, C. P. Adams, Y. Anaya, J. B. Singer et al., 2004 A complex interaction of imprinted and maternal-effect genes modifies sex determination in Odd Sex (Ods) mice. Genetics 168: 1557–1562. Reavey, C. T., M. J. Hickman, K. C. Dobi, D. Botstein, and F. Winston, 2015 Analysis of polygenic mutants suggests a role for mediator in regulating transcriptional activation distance in Saccharomyces cerevisiae. Genetics 201: 599–612. Schatz, P. J., F. Solomon, and D. Botstein, 1988 Isolation and characterization of conditional-lethal mutations in the TUB1 a-tubulin gene of the yeast Saccharomyces cerevisiae. Genetics 120: 681–695. Sekiya-Kawasaki, M., D. Botstein, and Y. Ohya, 1998 Identification of functional connections between calmodulin and the yeast actin cytoskeleton. Genetics 150: 43–58. Singer, J. B., A. E. Hill, J. H. Nadeau, and E. S. Lander, 2005 Mapping quantitative trait loci for anxiety in chromosome substitution strains of mice. Genetics 169: 855–862.
Stearns, T., and D. Botstein, 1988 Unlinked noncomplementation: isolation of new conditional-lethal mutations in each of the tubulin genes of Saccharomyces cerevisiae. Genetics 119: 249–260. Stearns, T., M. A. Hoyt, and D. Botstein, 1990 Yeast mutants sensitive to antimicrotubule drugs define three genes that affect microtubule function. Genetics 124: 251–262. Stuber, C. W., S. E. Lincoln, D. W. Wolff, T. Helentjaris, and E. S. Lander, 1992 Identification of genetic factors contributing to heterosis in a hybrid from two elite maize inbred lines using molecular markers. Genetics 132: 823–839. Thomas, J. H., and D. Botstein, 1987 Ordered linear tetrads are produced by the sporulation of newly formed zygotes of Saccharomyces cerevisiae. Genetics 115: 229–232. Thomas, J. H., N. F. Neff, and D. Botstein, 1985 Isolation and characterization of mutations in the b-tubulin gene of Saccharomyces cerevisiae. Genetics 111: 715–734. Weinstock, G. M., M. M. Susskind, and D. Botstein, 1979 Regional specificity of illegitimate recombination by the translocatable ampicillin-resistance element Tn1 in the genome of phage P22. Genetics 92: 685–710. Wertman, K. F., D. G. Drubin, and D. Botstein, 1992 Systematic mutational analysis of the yeast ACT1 gene. Genetics 132: 337– 350.
Communicating editor: C. Gelling
Classic
3
Eric Lander and David Botstein on Mapping Quantitative Traits Gary A. Churchill1 The Jackson Laboratory, Bar Harbor, Maine 04609
ORIGINAL CITATION Mapping Mendelian Factors Underlying Quantitative Traits Using RFLP Linkage Maps. Eric S. Lander and David Botstein GENETICS January 1, 1989 121: 185–199
T
he rediscovery of Mendel’s work in the early 20th century sparked heated debate about the inheritance of continuously variable “size” traits (e.g., East 1916). But, although evidence accumulated in support of Mendelian models of quantitative trait inheritance, for most of the century it was rare for geneticists to be able to link such traits to specific Mendelian factors. The principles of mapping quantitative traits to qualitative characters had been well understood since Sax (1923) established the linkage of seed size to pigmentation in beans. What was missing was a systematic method to identify the specific factors underlying quantitative traits, to estimate their effects, and to characterize their interactions. The foundation for change began with a proposal to develop genome-wide maps of restriction fragment length polymorphism (RFLP) markers in humans (Botstein et al. 1980). In principle, RFLP markers fell close enough together that the whole genome could be efficiently scanned for linkage to a trait of interest. But it was the landmark article of Lander and Botstein (1989) that brought together the power of model organism crosses with genome-wide RFLP maps and provided a systematic strategy for mapping the long sought factors or quantitative trait loci (QTL). The key innovation—known as interval mapping—is a statistical algorithm to use all of the information available in the genome-wide markers. This increased the power and precision of mapping in comparison to older methods that evaluated linkage one marker at a time. By bridging the gaps between markers, the Copyright © 2016 by the Genetics Society of America doi: 10.1534/genetics.116.189803 Image of Eric Lander (left) and David Botstein (right) courtesy of Cold Spring Harbor Laboratory Archives. 1Address for correspondence: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. E-mail: [email protected]
log-likelihood profiles obtained from interval mapping provided the first genome-wide view of the QTL landscape. Lander and Botstein (1989) is rich with ideas and open questions that fueled methodological research, including the problem of multiple testing in genome-wide searches (Churchill and Doerge 1994). Lander and Botstein (1989) also addressed practical questions of study design that inspired and empowered hundreds of applications of their method in agricultural, biomedical, and basic research in the decades that followed. Researchers were soon faced with new questions and challenges, however. QTL were numerous and the effort of isolating the causal genes and variants often proved to be daunting. Studies of blood pressure in the laboratory rat, for example, identified QTL on almost every chromosome (Rapp 2000). QTL could encompass multiple tightly linked variants; they were often dependent on genetic background or environmental contexts; their effects could be small or large, pleiotropic, additive, or epistatic. In an early and innovative application, Damerval and colleagues (1994) applied QTL mapping to the quantitative expression of proteins (Damerval et al. 1994). QTL mapping of molecular phenotypes has since revealed elaborate networks of genetic regulation. Application of Lander and Botstein’s method for isolating Mendelian factors has revealed the true magnitude of quantitative genetic complexity, confirming an expectation set forth a century ago by the first geneticists.
Literature Cited Botstein, D., R. L. White, M. Skolnick, and R. W. Davis, 1980 Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am. J. Hum. Genet. 32: 314–331.
Genetics, Vol. 203, 1–3 May 2016
1
Churchill, G. A., and R. W. Doerge, 1994 Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971. Damerval, C., A. Maurice, J. M. Josse, and D. de Vienne, 1994 Quantitative trait loci underlying gene product variation: a novel perspective for analyzing regulation of genome expression. Genetics 137: 289–301. East, E. M., 1916 Studies on size inheritance in Nicotiana. Genetics 1: 164–176. Rapp, J. P., 2000 Genetic analysis of inherited hypertension in the rat. Physiol. Rev. 80(1): 135–172. Sax, K., 1923 The association of size differences with seed-coat pattern and pigmentation in Phaseolus vulgaris. Genetics 8: 552–560.
Further Reading in GENETICS Dilda, C. L., and T. F. C. Mackay, 2002 The genetic architecture of Drosophila sensory bristle number. Genetics 162: 1655–1674. Hill, W. G., and T. F. C. Mackay, 2004 D. S. Falconer and introduction to quantitative genetics. Genetics 167: 1529–1536. Jansen, R. C., 1996 A general Monte Carlo method for mapping multiple quantitative trait loci. Genetics 142: 305–311. Sen, S., and G. A. Churchill, 2001 A statistical framework for quantitative trait mapping. Genetics 159: 371–387. Studer, A. J., and J. F. Doebley, 2011 Do large effect QTL fractionate? A case study at the maize domestication QTL teosinte branched1. Genetics 188: 673–681. Weiss, K. M., 2008 Tilting at quixotic trait loci (QTL): an evolutionary perspective on genetic causation. Genetics 179: 1741– 1756. Zeng, Z. B., 1994 Precision mapping of quantitative trait loci. Genetics 136: 1457–1468.
Other GENETICS Articles by E. S. Lander and D. Botstein Adams, A. E., and D. Botstein, 1989 Dominant suppressors of yeast actin mutations that are reciprocally suppressed. Genetics 121: 675–683. Botstein, D., 1992 1992 Genetics Society of America Medal: Maynard V. Olson. Genetics 131: S11–S12. Botstein, D., 2004 Ira Herskowitz: 1946–2003. Genetics 166: 653–660. Botstein, D., and G. R. Fink, 2011 Yeast: an experimental organism for 21st century biology. Genetics 189: 695–704. Brandriss, M. C., L. Soll, and D. Botstein, 1975 Recessive lethal amber suppressors in yeast. Genetics 79: 551–560. Carlson, M., B. C. Osmond, and D. Botstein, 1981a Mutants of yeast defective in sucrose utilization. Genetics 98: 25–40. Carlson, M., B. C. Osmond, and D. Botstein, 1981b Genetic evidence for a silent SUC gene in yeast. Genetics 98: 41–54. Carlson, M., B. C. Osmond, L. Neigeborn, and D. Botstein, 1984 A suppressor of SNF1 mutations causes constitutive high-level invertase synthesis in yeast. Genetics 107: 19–32. Caudy, A. A., Y. Guan, Y. Jia, C. Hansen, C. DeSevo et al., 2013 A new system for comparative functional genomics of Saccharomyces yeasts. Genetics 195: 275–287. Chan, C. S., and D. Botstein, 1993 Isolation and characterization of chromosome-gain and increase-in-ploidy mutants in yeast. Genetics 135: 677–691. Chan, R. K., and D. Botstein, 1976 Specialized transduction by bacteriophage P22 in Salmonella typhimurium: genetic and physical structure of the transducing genomes and the prophage attachment site. Genetics 83: 433–458.
2
G. A. Churchill
Dietrich, W., H. Katz, S. E. Lincoln, H. S. Shin, J. Friedman et al., 1992 A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131: 423–447. Falco, S. C., and D. Botstein, 1983 A rapid chromosome-mapping method for cloned fragments of yeast DNA. Genetics 105: 857– 872. Falco, S. C., M. Rose, and D. Botstein, 1983 Homologous recombination between episomal plasmids and chromosomes in yeast. Genetics 105: 843–856. Gould, K. A., W. F. Dietrich, N. Borenstein, E. S. Lander, and W. F. Dove, 1996a Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics 144: 1769–1776. Gould, K. A., C. Luongo, A. R. Moser, M. K. McNeley, N. Borenstein et al., 1996b Genetic evaluation of candidate genes for the Mom1 modifier of intestinal neoplasia in mice. Genetics 144: 1777–1785. Gresham, D., V. M. Boer, A. Caudy, N. Ziv, N. J. Brandt et al., 2011 System-level analysis of genes and functions affecting survival during nutrient starvation in Saccharomyces cerevisiae. Genetics 187: 299–317. Heck, J. A., D. Gresham, D. Botstein, and E. Alani, 2006 Accumulation of recessive lethal mutations in Saccharomyces cerevisiae mlh1 mismatch repair mutants is not associated with gross chromosomal rearrangements. Genetics 174: 519– 523. Huisman, O., W. Raymond, K. U. Froehlich, P. Errada, N. Kleckner et al., 1987 A Tn10-lacZ-kanR-URA3 gene fusion transposon for insertion mutagenesis and fusion analysis of yeast and bacterial genes. Genetics 116: 191–199. Hulbert, S. H., T. W. Ilott, E. J. Legg, S. E. Lincoln, E. S. Lander et al., 1988 Genetic analysis of the fungus, Bremia lactucae, using restriction fragment length polymorphisms. Genetics 120: 947–958. Kleckner, N., D. F. Barker, D. G. Ross, and D. Botstein, 1978 Properties of the translocatable tetracycline-resistance element Tn10 in Escherichia coli and bacteriophage lambda. Genetics 90: 427–461. Kleckner, N., D. A. Steele, K. Reichardt, and D. Botstein, 1979 Specificity of insertion by the translocatable tetracycline-resistance element Tn10. Genetics 92: 1023–1040. Kruglyak, L., and E. S. Lander, 1995 A nonparametric approach for mapping quantitative trait loci. Genetics 139: 1421–1428. Kunes, S., H. Ma, K. Overbye, M. S. Fox, and D. Botstein, 1987 Fine structure recombinational analysis of cloned genes using yeast transformation. Genetics 115: 73–81. Kunes, S., D. Botstein, and M. S. Fox, 1990 Synapsis-mediated fusion of free DNA ends forms inverted dimer plasmids in yeast. Genetics 124: 67–80. Lang, G. I., D. Botstein, and M. M. Desai, 2011 Genetic variation and the fate of beneficial mutations in asexual populations. Genetics 188: 647–661. Maurer, R., B. C. Osmond, and D. Botstein, 1984a Genetic analysis of DNA replication in bacteria: dnaB mutations that suppress dnaC mutations and dnaQ mutations that suppress dnaE mutations in Salmonella typhimurium. Genetics 108: 25–38. Maurer, R., B. C. Osmond, E. Shekhtman, A. Wong, and D. Botstein, 1984b Functional interchangeability of DNA replication genes in Salmonella typhimurium and Escherichia coli demonstrated by a general complementation procedure. Genetics 108: 1–23. Moir, D., and D. Botstein, 1982 Determination of the order of gene function in the yeast nuclear division pathway using cs and ts mutants. Genetics 100: 565–577. Moir, D., S. E. Stewart, B. C. Osmond, and D. Botstein, 1982 Coldsensitive cell-division-cycle mutants of yeast: isolation, properties, and pseudoreversion studies. Genetics 100: 547–563.
Novick, P., B. C. Osmond, and D. Botstein, 1989 Suppressors of yeast actin mutations. Genetics 121: 659–674. Ohya, Y., and D. Botstein, 1994 Structure-based systematic isolation of conditional-lethal mutations in the single yeast calmodulin gene. Genetics 138: 1041–1054. Paterson, A. H., S. Damon, J. D. Hewitt, D. Zamir, H. D. Rabinowitch et al., 1991 Mendelian factors underlying quantitative traits in tomato: comparison across species, generations, and environments. Genetics 127: 181–197. Poirier, C., Y. Qin, C. P. Adams, Y. Anaya, J. B. Singer et al., 2004 A complex interaction of imprinted and maternal-effect genes modifies sex determination in Odd Sex (Ods) mice. Genetics 168: 1557–1562. Reavey, C. T., M. J. Hickman, K. C. Dobi, D. Botstein, and F. Winston, 2015 Analysis of polygenic mutants suggests a role for mediator in regulating transcriptional activation distance in Saccharomyces cerevisiae. Genetics 201: 599–612. Schatz, P. J., F. Solomon, and D. Botstein, 1988 Isolation and characterization of conditional-lethal mutations in the TUB1 a-tubulin gene of the yeast Saccharomyces cerevisiae. Genetics 120: 681–695. Sekiya-Kawasaki, M., D. Botstein, and Y. Ohya, 1998 Identification of functional connections between calmodulin and the yeast actin cytoskeleton. Genetics 150: 43–58. Singer, J. B., A. E. Hill, J. H. Nadeau, and E. S. Lander, 2005 Mapping quantitative trait loci for anxiety in chromosome substitution strains of mice. Genetics 169: 855–862.
Stearns, T., and D. Botstein, 1988 Unlinked noncomplementation: isolation of new conditional-lethal mutations in each of the tubulin genes of Saccharomyces cerevisiae. Genetics 119: 249–260. Stearns, T., M. A. Hoyt, and D. Botstein, 1990 Yeast mutants sensitive to antimicrotubule drugs define three genes that affect microtubule function. Genetics 124: 251–262. Stuber, C. W., S. E. Lincoln, D. W. Wolff, T. Helentjaris, and E. S. Lander, 1992 Identification of genetic factors contributing to heterosis in a hybrid from two elite maize inbred lines using molecular markers. Genetics 132: 823–839. Thomas, J. H., and D. Botstein, 1987 Ordered linear tetrads are produced by the sporulation of newly formed zygotes of Saccharomyces cerevisiae. Genetics 115: 229–232. Thomas, J. H., N. F. Neff, and D. Botstein, 1985 Isolation and characterization of mutations in the b-tubulin gene of Saccharomyces cerevisiae. Genetics 111: 715–734. Weinstock, G. M., M. M. Susskind, and D. Botstein, 1979 Regional specificity of illegitimate recombination by the translocatable ampicillin-resistance element Tn1 in the genome of phage P22. Genetics 92: 685–710. Wertman, K. F., D. G. Drubin, and D. Botstein, 1992 Systematic mutational analysis of the yeast ACT1 gene. Genetics 132: 337– 350.
Communicating editor: C. Gelling
Classic
3
