Leonid Kruglyak

This email address is being protected from spambots. You need JavaScript enabled to view it.	Kruglyak Research Lab
(609) 258-9209	Carl Icahn Lab, 143
	Lab (609) 258-9209
Faculty Assistant	Faith Bahadurian
This email address is being protected from spambots. You need JavaScript enabled to view it.	(609) 258-3731

Research Focus

Genetic Basis of Phenotypic Variation

I am interested in the genetic basis of heritable traits. The genetic basis of most traits is complex, involving many genes that interact with each other and the environment. My lab conducts experiments in model organisms (the yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans), as well as computational analyses, aimed at understanding how changes at the level of DNA are shaped by molecular and evolutionary forces, and how these changes lead to all the observable differences among individuals within a species.

Genetics of global gene expression in S. cerevisiae

Genetic background affects expression of a substantial fraction of all genes. We have carried out extensive analysis of genome-wide expression levels in a cross between two diverse yeast strains. We were able to link expression levels of thousands of genes to genetic markers, and to show that expression of most genes is genetically complex, with multiple loci involved in determining expression levels. We also found large groups of genes of related function, with expression levels of all members of a group linking to the same locus, and identified specific polymorphisms responsible for these expression differences. We developed new statistical methods to search for naturally occurring genetic interactions underlying gene expression, and identified such interactions for many transcripts. Ongoing research projects include: investigating the interactions between genes and environment in control of cell growth and gene expression; studying the genetics of sensitivity and resistance to drugs and other chemical compounds; understanding the genetic basis of variation in protein levels; and investigating strain-specific phenotypic effects of prion-like elements in yeast.

Technology development and yeast population genetics

One of the central challenges of genomics is to be able to detect, simply and cheaply, all differences in sequence among the genomes of individual members of a species. We devised a system that detects ~90% of all single-nucleotide differences in yeast genomes and maps them to within a few nucleotides on a reference sequence. This system makes it possible to find a variety of single spontaneous mutations in different genes, gene-size insertions and deletions, and most single-nucleotide polymorphisms between diverse yeast strains. We are using this system to characterize the genomic diversity of a large collection of yeast strains sampled from all over the world and from different ecological niches. We plan to extend these studies to connect sequence variation across the species with variation in gene expression, ecological niche, and other phenotypes. Relatively little is known about the natural lifestyle and population genetics of yeast. One major question is whether genetically diverse yeast strains mate and recombine in the wild. We developed a method to infer the evolutionary history of a species from genome sequences of multiple individuals and applied it to whole-genome sequence data from three strains of S. cerevisiae and the sister species S. paradoxus. We estimated that although any two strains have undergone approximately 16 million cell divisions since their last common ancestor, only 314 outcrossing events have occurred during this time (roughly one every 50,000 divisions). These results provide the initial foundation for population studies of association between genotype and phenotype in S. cerevisiae.

Complex trait genetics in C. elegans

We have built a set of over 200 advanced intercross inbred lines from a cross between the Bristol and Hawaiian isolates. We densely genotyped these lines to delineate the contributions of each parental genome to each line. The lines are being phenotyped for gene expression as well as morphological, developmental, and behavioral traits, allowing us to investigate the genetic basis of variation in these traits. We have also noted a region of the genome that was subject to selection during line construction, and shown that this is due to an incompatibility between the parental isolate alleles at two loci. This appears to be an incipient speciation event between the isolates. We are pursuing an investigation into the molecular nature of this effect. In addition to the inbred lines, we have genotyped a large collection of wild C. elegans isolates, which allows us to investigate worm population genetics and determine the evolutionary history of polymorphisms with phenotypic effects.

Selected Publications

Bloom JS, Ehrenreich IM, Loo WT, Lite TL, Kruglyak L. (2013) Finding the sources of missing heritability in a yeast cross. Nature. 494: 234-7. Pubmed

Khan Z, Bloom JS, Amini S, Singh M, Perlman DH, Caudy AA, Kruglyak L. (2012) Quantitative measurement of allele-specific protein expression in a diploid yeast hybrid by LC-MS. Mol Syst Biol. 8: 602. Pubmed

Reaves ML, Sinha S, Rabinowitz JD, Kruglyak L, Redfield RJ. (2012) Absence of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells. Science. 337: 470-473. Pubmed

Andersen EC, Gerke JP, Shapiro JA, Crissman JR, Ghosh R, Bloom JS, Félix MA, Kruglyak L. (2012) Chromosome-scale selective sweeps shape Caenorhabditis elegans genomic diversity. Nat Genet.  44: 285-290. PubMed

Ehrenreich IM, Bloom J, Torabi N, Wang X, Jia Y, Kruglyak L. (2012) Genetic architecture of highly complex chemical resistance traits across four yeast strains. PLoS Genet. 8: e1002570. PubMed

Torabi N, Kruglyak L. (2012) Genetic basis of hidden phenotypic variation revealed by increased translational readthrough in yeast. PLoS Genet. 8: e1002546. PubMed

Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L. (2012) Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans. Science. 335: 574-578. PubMed

Khan Z, Amini S, Bloom JS, Ruse C, Caudy AA, Kruglyak L, Singh M, Perlman DH, Tavazoie S. (2011) Accurate proteome-wide protein quantification from high-resolution 15N mass spectra. Genome Biol. 12: R122. Pubmed

Torabi N, Kruglyak L. (2011) Variants in SUP45 and TRM10 underlie natural variation in translation termination efficiency in Saccharomyces cerevisiae. PLoS Genet. 7: e1002211. PubMed

Seidel HS, Ailion M, Li J, van Oudenaarden A, Rockman MV, Kruglyak L. (2011) A novel sperm-delivered toxin causes late-stage embryo lethality and transmission ratio distortion in C. elegans. PLoS Biol. 9: e1001115. PubMed

Ehrenreich IM, Torabi N, Jia Y, Kent J, Martis S, Shapiro JA, Gresham D, Caudy AA, Kruglyak L. (2010) Dissection of genetically complex traits with extremely large pools of yeast segregants. Nature. 464: 1039-1042. PubMed

Gresham D, Curry B, Ward A, Gordon DB, Brizuela L, Kruglyak L, Botstein D. (2010) Optimized detection of sequence variation in heterozygous genomes using DNA microarrays with isothermal-melting probes. Proc Natl Acad Sci. 107: 1482-1487. PubMed

Ehrenreich IM, Gerke JP, Kruglyak L. (2009) Genetic dissection of complex traits in yeast: Insights from studies of gene expression and other phenotypes in the BYxRM cross. Cold Spring Harb Symp Quant Biol. 74: 145-153. PubMed

Khan Z, Bloom JS, Garcia BA, Singh M, Kruglyak L. (2009) Protein quantification across hundreds of experimental conditions. Proc Natl Acad Sci. 106: 15544-15548. PubMed

Bloom JS, Khan Z, Kruglyak L, Singh M, Caudy AA. (2009) Measuring differential gene expression by short read sequencing: quantitative comparison to 2-channel gene expression microarrays. BMC Genomics 10: 221. PubMed

Khan Z, Bloom JS, Kruglyak L, Singh M. (2009) A practical algorithm for finding maximal exact matches in large sequence data sets using sparse suffix arrays. Bioinformatics. 25: 1609-1616. PubMed

Rockman MV, Kruglyak L. (2009) Recombinational landscape and population genomics of Caenorhabditis elegans. PLoS Genet. 5: e1000419. PubMed

Schacherer J, Shapiro JA, Ruderfer DM, Kruglyak L. (2009) Comprehensive polymorphism survey elucidates population structure of Saccharomyces cerevisiae. Nature 458: 342-345. PubMed

Capra EJ, Skrovanek SM, Kruglyak L. (2008) Comparative developmental expression profiling of two C. elegans isolates. PLoS ONE. 3: e4055. PubMed

Coller HA, Kruglyak L. (2008) Genetics. It's the sequence, stupid! Science 322: 380-381. PubMed

Gresham D, Kruglyak L. (2008) Rise of the machines. PLoS Genet. 4: e1000134. PubMed

Rockman MV, Kruglyak L. (2008) Breeding designs for recombinant inbred advanced intercross lines. Genetics 179: 1069-1078. PubMed

Smith EN, Kruglyak L. (2008) Gene-environment interaction in yeast gene expression. PLoS Biol. 6: e83. PubMed

Kruglyak L. (2008) The road to genome-wide association studies. Nat Rev Genet. 9: 314-318. PubMed

Seidel HS, Rockman MV, Kruglyak L. (2008) Widespread genetic incompatibility in C. Elegans maintained by balancing selection. Science 319: 589-594. PubMed

Kruglyak L, Stern DL. (2007) Evolution. An embarrassment of switches. Science 317: 758-759. PubMed

Schacherer J, Ruderfer DM, Gresham D, Dolinski K, Botstein D, Kruglyak L. (2007) Genome-wide analysis of nucleotide-level variation in commonly used Saccharomyces cerevisiae strains. PLoS ONE 2: e322. PubMed

Rockman MV, Kruglyak L. (2006) Genetics of global gene expression. Nat Rev Genet 7: 862-782. PubMed

Ruderfer DM, Pratt SC, Seidel HS, Kruglyak L. (2006) Population genomic analysis of outcrossing and recombination in yeast. Nat Genet 38: 1077-1081. PubMed

Gresham D, Ruderfer DM, Pratt SC, Schacherer J, Dunham MJ, Botstein D, Kruglyak L. (2006) Genome-wide detection of polymorphisms at nucleotide resolution with a single DNA microarray. Science 311: 1932-1936. PubMed

Perlstein EO, Ruderfer DM, Ramachandran G, Haggarty SJ, Kruglyak L, Schreiber SL. (2006) Revealing complex traits with small molecules and naturally recombinant yeast strains. Chem Biol 13: 319-327. PubMed

Ronald J, Brem RB, Whittle J, Kruglyak L. (2005) Local regulatory variation in Saccharomyces cerevisiae. PLoS Genet 1: e25. PubMed

Brem RB, Storey JD, Whittle J, Kruglyak L. (2005) Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436: 701-703. PubMed

Storey JD, Akey JM, Kruglyak L. (2005) Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biol 3: e267. PubMed

Ronald J, Akey JM, Whittle J, Smith EN, Yvert G, Kruglyak L. (2005) Simultaneous genotyping, gene-expression measurement, and detection of allele-specific expression with oligonucleotide arrays. Genome Res 15: 284-291. PubMed

Brem RB, Kruglyak L. (2005) The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc Natl Acad Sci USA 102: 1572-1577. PubMed

Parker HG, Kim LV, Sutter NB, Carlson S, Lorentzen TD, Malek TB, Johnson GS, DeFrance HB, Ostrander EA, Kruglyak L. (2004) Genetic structure of the purebred domestic dog. Science 304: 1160-1164. PubMed

Akey JM, Eberle MA, Rieder MJ, Carlson CS, Shriver MD, Nickerson DA, Kruglyak L. (2004) Population history and natural selection shape patterns of genetic variation in 132 genes. PLoS Biol 2: e286. PubMed

Yvert G, Brem RB, Whittle J, Akey JM, Foss E, Smith EN, Mackelprang R, Kruglyak L. (2003) Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat Genet 35: 57-64. PubMed

Niare O, Markianos K, Volz J, Oduol F, Toure A, Bagayoko M, Sangare D, Traore SF, Wang R, Blass C, Dolo G, Bouare M, Kafatos FC, Kruglyak L, Toure YT, Vernick KD. (2002) Genetic loci affecting resistance to human malaria parasites in a West African mosquito vector population. Science 298: 213-296. PubMed

Brem RB, Yvert G, Clinton R, Kruglyak L. (2002) Genetic dissection of transcriptional regulation in budding yeast. Science 296: 752-755. PubMed