FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2088495596> ?p ?o ?g. }

• W2088495596 endingPage "327" @default.
• W2088495596 startingPage "318" @default.
• W2088495596 abstract "Thank you, Terry, for that introduction; and my deep thanks to the Awards Committee and to all of you for the award you have given me this afternoon. I am so grateful for and humbled by this honor. I am grateful because of your willingness to recognize the achievements of a large group of hardworking individuals who have worked and played in what we've called The Sandbox for the past 27 years. And humbled because I recognize that the list of people I now join is such a profoundly distinguished one. This is a wonderful group to now be part of, and I'm deeply grateful to The Society and to the Awards Committee for that honor. I'm so pleased to join my chromosome colleagues Pat Jacobs, Dorothy Warburton, and, of course, Mary Lyon, and a whole host of other individuals whom I've spent so much of my career looking up to. I'm also thrilled to share this afternoon with Janet Rowley, this year's winner of the Gruber Prize in Genetics. Between the Allan Award, the Gruber Prize, and the Nobel Prize for telomeres a week ago, it's been a pretty good month for chromosomes! At the risk of giving away the punch line at the beginning, my comments this afternoon about the last 30-plus years of my scientific life will be less a personal tale of my own career than they are a tale of students and mentors, their achievements, their motivations, and the insights they've brought to their work. It's a story of young scientists who at the very early stages of their careers are empowered to take ownership of science, to take a question, to put their mark on it, and to decide what they want to do with it. Not what I wanted to do with it or what the field wanted to do with it, but what each of these students wanted to do with it—students validated in their search for trying to figure out answers to a series of questions that perhaps only they know, as they've articulated it (or perhaps haven't even yet fully articulated) to themselves. Whatever successes I've enjoyed are most directly a reflection of the opportunities I was given very early on in my own training. If I've had success since starting my own group, it's been success in creating an environment in which students could come into The Sandbox—whether graduate students, postdoctoral fellows, or, now increasingly, undergraduates—and could find an opportunity to be validated as scientists, to realize that a lifetime of discovery is one of the greatest privileges that one can have in science. Such an awakening is not something that comes naturally to many students, because there's nothing in our general society and certainly little in our educational system in its earliest stages that prepares students for the recognition of what a life of science and a life of discovery is all about and for the sense of empowerment that comes with that. So this is a story of students, my students. But I start with a story of another student some 36 years ago. This story begins on October 31, 1973, almost exactly 36 years ago. Now, you might say, “How did he ever remember that that was the date?” Well, I know that was the date because I actually keep my notebooks! I was taking Biology 113 then in college, a course on human genetics that used the “red book,” the textbook by Curt Stern that remains, in my view, the best textbook on human genetics that has ever been written and certainly the book that opened this field up to me.1Stern C. Principles of Human Genetics.Third Edition. W.H. Freeman and Company, San Francisco1973Google Scholar On October 31, 1973, we had a lecture on X inactivation. And as I took my notes that day (Figure 1)—and believe me, my handwriting was a whole lot better 36 years ago than it is now!—I began to realize that this was an unbelievably interesting and what I would come to call a “chewy” problem—a problem that had absolutely no precedent to suggest an answer, no set of guidelines or rules that we could understand at that time or that we could use to even begin to think about the problem. This was a wonderful time in human genetics, as those of you who are of that vintage will recognize. Mary Lyon herself had only written about X inactivation a dozen years before this,2Lyon M.F. Gene action in the X-chromosome of the mouse (Mus musculus L.).Nature. 1961; 190: 372-373Crossref PubMed Scopus (2452) Google Scholar and this was a period of time, especially in human cytogenetics, during which the community of human and medical geneticists was trying to figure out just how relevant the idea of X chromosome inactivation might be to our field. As seen through the eyes of an impressionable young student, several spectacularly insightful and inviting papers were published at that time, gray and dusty copies of which I still lug around in my now heavily dog-eared file on X inactivation. Brown and Chandra's idea for how the X inactivation center works3Brown S.W. Chandra H.S. Inactivation system of the mammalian X chromosome.Proc. Natl. Acad. Sci. USA. 1973; 70: 195-199Crossref PubMed Scopus (59) Google Scholar still remains one of the most lucid models of random X inactivation, and several reviews by Eva Therman and Klaus Patau4Therman E. Patau K. Abnormal X chromosomes in man: origin, behavior and effects.Humangenetik. 1974; 25: 1-16PubMed Google Scholar, 5Therman E. Sarto G.E. Patau K. Center for Barr body condensation on the proximal part of the human Xq: a hypothesis.Chromosoma. 1974; 44: 361-366Crossref PubMed Scopus (61) Google Scholar served as both an introduction and the bridge that would bring X inactivation and chromosomes together for me. So how was a young student going to get started? At that stage, and this was now early spring of 1974, I did what I thought all students would do, although I realize in retrospect that that wasn't necessarily true. I just picked up the phone and called the head of the Clinical Genetics Division at Children's Hospital and asked to speak to Park Gerald. Can you imagine? When that happens to me now and students call or email me, I try to remember that day in 1974 and try to be as generous with my time as Park was with me. That very day, he came on the phone and wanted to know who I was. Without hesitation, I asked if there were any opportunities to work in a laboratory that summer, because human genetics was going to be my future. Well, he deigned to meet with me a few days later, and after chatting with me for about 10 or 15 minutes, he said “Wait here,” and he went down the hall to grab Sam Latt. Sam had published a paper6Latt S.A. Microfluorometric detection of deoxyribonucleic acid replication in human metaphase chromosomes.Proc. Natl. Acad. Sci. USA. 1973; 70: 3395-3399Crossref PubMed Scopus (739) Google Scholar just a few months before, his first paper laying out the principles of using bromodeoxyuridine (BrdU) as a measure for the timing of replication based on the interactions between BrdU and the dye 33258 Hoechst, a method that revolutionized the study of chromosomes and allowed fluorescence detection of DNA replication instead of the hideously painful technique of autoradiography, which was in use up to that time. I joined Sam's lab that afternoon and spent the next 18 months working under his tutelage at an incredibly exciting time when, although I didn't realize it at the time, I was allowed to be at the breaking edge of a wave, working with him trying to figure out the patterns of X inactivation and DNA replication on the active and inactive X chromosomes in female cells, at a level of resolution and with a level of precision that just simply hadn't been possible previously. Under very different and far more difficult circumstances, I've written elsewhere7Willard H.F. In memory of Samuel A. Latt, M.D. Ph.D.Am. J. Hum. Genet. 1989; 44: 766-767Google Scholar about those times in his lab, but the thoughts are just as meaningful and relevant today:One of the potentially most rewarding by-products of our business is the strong, mutually supportive relationship that often develops between mentor and student. Some are personal, others intellectual; in some cases, the distinction blurs. In the most favorable instances, the mentor provides leadership, guidance, and inspiration, in return for satisfaction from setting a young colleague on the “right” path. For his [or her] part, the student benefits from the opportunity, when done right, to learn excellence and passion at a time when one's the most impressionable. The first teacher-student relationship has a unique flavor. Like other first encounters, it cannot be repeated, and its lessons – either good or bad – are most apt to be lasting ones…Since I had my first exposure to research in Sam's lab at a time of great excitement in cytogenetics, it is difficult to know how things might have turned out if he had not been willing to take a chance on a very green undergraduate and to share his sense of passion for chromosomes and discovery. I remember hours spent in the pitch darkness of the darkroom, waiting for autoradiographic emulsion to dry on dipped slides, listening to Sam go on about the latest in chromosome structure, X inactivation, or clinical cytogenetics. For a wide-eyed student fumbling in the dark, those sessions were profoundly stimulating. The experience of working with Sam has…had a lasting influence on the directions of our research and our thinking. Sam and I published a paper early in 1976, my first paper in The American Journal of Human Genetics, and it remains one of the papers of which I'm most proud.8Willard H.F. Latt S.A. Analysis of DNA replication in human X chromosomes by fluorescence microscopy.Am. J. Hum. Genet. 1976; 28: 213-227PubMed Google ScholarFigure 2 illustrates these active X and inactive X replication patterns, from one of the slides that I presented in my ten-minute talk at the October 1975 meeting of this Society, the first of my ASHG meetings. But I show it here again because there are parts of this story that, even some 35 years later, we still don't understand; every time I look at that picture of DNA replication on the active and inactive X chromosomes in female cells, I am struck by the size of the segments of the X chromosome—some 20 to 30 Mb of DNA—that coordinately shift their time of replication in S phase. We still don't have a clue in 2009 how that happens! But hopefully, with the ENCODE (Encyclopedia of DNA Elements) project and an increasing technological capability for studying questions like this, we will begin to understand what features of our genome and chromosomes control the timing of replication and, as a consequence of that, begin to understand what it is about the epigenetic control of X inactivation that so fundamentally shifts the replication behavior of the inactive X chromosome. Some still unfinished business. As I completed my undergraduate work with Sam, and with my interest in human genetics, I searched around the country for graduate programs that would allow me to do what I wanted to do, which was, of course, to continue to study X inactivation. After a brief flirtation with Stan Gartler that almost took me to the west coast, I ended up going to Yale for a four-year side trip into inborn errors of metabolism, studying with Leon Rosenberg. While I recall being disappointed that each new disorder in cobalamin (vitamin B12) metabolism being defined then turned out to be autosomal and not X-linked, this was a wonderful time for me because, even though my Ph.D. projects weren't directly connected to X inactivation, it was exposure to biochemical genetics that has allowed me to appreciate much more deeply the rich nuances of the field of human genetics and to think much more broadly about genetics than I would have if I had stayed glued to chromosomes for my entire career. At Yale, I benefitted enormously from the mentorship of Lee Rosenberg. As I commented in my ASHG Presidential Address eight years ago,9Willard H.F. 2001 ASHG Presidential Address. On black boxes and storytellers: lessons learned in human genetics.Am. J. Hum. Genet. 2002; 70: 285-296Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar there's nothing in my career that I've achieved that I don't ultimately give him credit for. In reality, I actually had two mentors at Yale, one being Lee and the other Roy Breg, who directed the clinical cytogenetics lab at Yale at that time. It was Roy who allowed me to continue to work on X inactivation late in the evenings, and we were able to publish a few papers on that work at that time,10Willard H.F. Tissue-specific heterogeneity in DNA replication patterns of human X chromosomes.Chromosoma. 1977; 61: 61-73Crossref PubMed Scopus (52) Google Scholar, 11Willard H.F. Breg W.R. Human X chromosomes: synchrony of DNA replication in diploid and triploid fibroblasts with multiple active or inactive X chromosomes. Somat.Cell Genet. 1980; 6: 187-198Crossref Scopus (11) Google Scholar allowing me to keep my fingers connected to the X chromosome. Roy was important to me for another reason too, as he had the great wisdom to hire as a cytogeneticist in his lab Vicki Powers, my wife now of some 30 years. It was love at first sight when I met Vicki, because she had what every 25-year-old, red-blooded American male would want—she had a microscope, which I desperately needed to carry out my studies! So, that was a match made in heaven, and the rest is history. In January 1982, I took up a faculty position at the University of Toronto, and The Sandbox officially opened (although, I now realize, no one can actually remember when we started calling it that!), with the goal of tackling X inactivation. My office in Toronto from the very early days had a cartoon on the wall that I've always loved, because it represented then (and to a certain extent even now) what I felt we knew about X inactivation (Figure 3). In starting out the lab at that time—and remember, this was some two decades before we'd have the human genome sequence—I developed a plan (hatched, as I recall, in discussions with Lee Rosenberg, walking on the shore near his house on Long Island Sound) to isolate DNA sequences from the X chromosome and, in my way of thinking, to use that to identify and clone genes that either were subject to or escaped from X inactivation. It was then that the very first examples of genes escaping from inactivation were becoming known, and these seemed to represent a promising avenue for understanding the chromosomal basis for X inactivation. What seemed then like a very straightforward plan turned into a much more convoluted but exciting path that has taken us into many different aspects of X inactivation, chromosome biology, and medical genetics over the ensuing 27 years (Figure 4). The early strategy to develop approaches for mapping cloned DNA and studying the expression of genes along the chromosome grew into a series of studies that are still being carried on today in our group with ever-changing technologies to derive X inactivation profiles in females for different genes that escape or are subject to inactivation. This led us more deeply into the genomics of the X chromosome, into sex chromosome evolution, and into thinking about the different medical consequences of genetic imbalance for either short-arm or long-arm abnormalities of the X chromosome. It also allowed us more recently to gain insight into the extraordinary amount of variability that exists between females in the population with respect to X-linked gene expression, the genetic and genomic basis of which we're still trying to understand. Many of the studies of the X chromosome in The Sandbox began with Carolyn Brown, who joined my lab as a graduate student in those early years in Toronto. It was she who had the original insight to recognize a gene that escaped X inactivation in a location that suggested that there could be many more such genes up and down the length of the chromosome, not just in the pseudoautosomal region or even in the ancient pseudoautosomal region.12Brown C.J. Willard H.F. Localization of a gene that escapes inactivation to the X chromosome proximal short arm: implications for X inactivation.Am. J. Hum. Genet. 1990; 45: 273-279Google Scholar She later was instrumental in recruiting Laura Carrel to the lab, and together they came up with a much larger number of genes that escaped inactivation not only on the proximal short arm but also on the long arm of the X.13Brown C.J. Carrel L. Willard H.F. Expression of genes from the human active and inactive X chromosomes.Am. J. Hum. Genet. 1997; 60: 1333-1343Abstract Full Text PDF PubMed Scopus (91) Google Scholar Carolyn and Laura brought great energy and persistence to what has turned into a multistudent and multidecade project, realizing over time that it would take 1200 genes, not just 12, to finally establish the genomic, chromosomal, and evolutionary basis for these X inactivation profiles. Yet more unfinished business! As a graduate student at Stanford, Laura took this project on and established what was then the first-generation X inactivation profile.14Carrel L. Cottle A.A. Goglin K.C. Willard H.F. A first-generation X-inactivation profile of the human X chromosome.Proc. Natl. Acad. Sci. USA. 1999; 96: 14440-14444Crossref PubMed Scopus (296) Google Scholar Andy Miller, another Stanford graduate student, defined regions on the X chromosome in which there were multiple genes clustered in a domain of several hundred kilobases in which all of the genes escaped inactivation.15Miller A.P. Willard H.F. Chromosomal basis of X chromosome inactivation: identification of a multigene domain in Xp11.21-p11.22 that escapes X inactivation.Proc. Natl. Acad. Sci. USA. 1998; 95: 8709-8714Crossref PubMed Scopus (69) Google Scholar This clustering suggested that there was something about the genomic sequence or organization of the chromosome itself that was controlling or contributing to the epigenetic result of X inactivation or escape from X inactivation. Before she was done, Laura ended up analyzing some nearly 800 genes on the chromosome16Carrel L. Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females.Nature. 2005; 434: 400-404Crossref PubMed Scopus (1346) Google Scholar in work that was published at the same time as the 155 Mb sequence of the X chromosome just a few years ago.17Ross M.T. Grafham D.V. Coffey A.J. Scherer S. McLay K. Muzny D. Platzer M. Howell G.R. Burrows C. Bird C.P. et al.The DNA sequence of the human X chromosome.Nature. 2005; 434: 325-337Crossref PubMed Scopus (752) Google Scholar The other part of the story for X inactivation, of course, is not just profiling X-linked gene expression, but determining the identity and nature of the X inactivation center, one of the big questions raised initially by Mary Lyon during the early 1960s.18Lyon, M.F. (1964). Second International Conference on Congenital Malformations, Session I, Discussion, pp. 67–68. New York: International Medical Congress Ltd.Google Scholar As originally outlined by Eva Therman in some of the early papers4Therman E. Patau K. Abnormal X chromosomes in man: origin, behavior and effects.Humangenetik. 1974; 25: 1-16PubMed Google Scholar, 5Therman E. Sarto G.E. Patau K. Center for Barr body condensation on the proximal part of the human Xq: a hypothesis.Chromosoma. 1974; 44: 361-366Crossref PubMed Scopus (61) Google Scholar I read as an undergraduate, it was clear that human cytogenetic material would be critical for helping the field identify where the X inactivation center was and how it might function. After a number of years of finding and characterizing abnormal X chromosomes, this line of reasoning led to the identification of the XIST gene, another story that began with Carolyn Brown. Working with Jim Rupert and Ron Lafreniere and then later with Brian Hendrich, another graduate student in the lab, Carolyn championed our early studies of the X inactivation center region19Brown C.J. Lafreniere R.G. Powers V.E. Sebastio G. Ballabio A. Pettigrew A.L. Ledbetter D.H. Levy E. Craig I.W. Willard H.F. Localization of the X inactivation centre on the human X chromosome in Xq13.Nature. 1991; 349: 82-84Crossref PubMed Scopus (291) Google Scholar and pursued a positional cloning strategy, using candidate DNA or cDNA clones from various regions of the X chromosome. These candidate clones had been sent to us by helpful X chromosome colleagues around the world, most especially in this case including Andrea Ballabio (then at Baylor College of Medicine), who provided the initial candidate cDNA and whose group helped with the initial characterization of XIST, once we had found it. Carolyn and her team identified and fully explored XIST's eponymous feature,20Brown C.J. Ballabio A. Rupert J.L. Lafreniere R.G. Grompe M. Tonlorenzi R. Willard H.F. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.Nature. 1991; 349: 38-44Crossref PubMed Scopus (1077) Google Scholar, 21Brown C.J. Hendrich B.D. Rupert J.L. Lafrenière R.G. Xing Y. Lawrence J. Willard H.F. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus.Cell. 1992; 71: 527-542Abstract Full Text PDF PubMed Scopus (940) Google Scholar its inactive-X-specific transcription, whether that inactive X was found in normal females or in males carrying more than just a single X, as in Klinefelter syndrome.20Brown C.J. Ballabio A. Rupert J.L. Lafreniere R.G. Grompe M. Tonlorenzi R. Willard H.F. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.Nature. 1991; 349: 38-44Crossref PubMed Scopus (1077) Google Scholar Carolyn had thus identified a gene expressed only from the inactive X and lying in the genetically and cytogenetically defined X inactivation center region, an obvious and strong candidate for a functional component of the X inactivation center itself. But how might it work? As she and I worked on the initial manuscripts to get them submitted to Nature in October of 1990 prior to her revealing the data for the first time at a workshop at the ASHG meeting that fall, we realized that a cis-acting functional RNA on the inactive X would be a more likely model than a protein product. Despite not having yet cloned or sequenced the full XIST RNA product (which, after all, was some 17 kb long), we proposed “that the XIST product is a cis-acting RNA molecule, perhaps involved structurally in formation of the heterochromatic Barr body.”20Brown C.J. Ballabio A. Rupert J.L. Lafreniere R.G. Grompe M. Tonlorenzi R. Willard H.F. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.Nature. 1991; 349: 38-44Crossref PubMed Scopus (1077) Google Scholar This was the first long noncoding RNA to be implicated as having a particular function in human cells and, together with Shirley Tilghman's discovery of the H19 RNA,22Brannan C.I. Dees E.C. Ingram R.S. Tilghman S.M. The product of the H19 gene may function as an RNA.Mol. Cell. Biol. 1990; 10: 28-36Crossref PubMed Scopus (787) Google Scholar provided early examples of the role of noncoding RNAs in epigenetic regulation. Having the XIST gene in hand and understanding the beginnings of the X inactivation center enabled us to pursue two different kinds of studies: first, studying skewed patterns of inactivation in females, different ratios that could differ significantly from the random 50:50 “coin flip” expected from the Lyon Hypothesis, and second, exploring the epigenetic control of gene expression on the X, studies that have moved into the field of chromatin and epigenetics, focusing on noncoding RNAs as well as histone variants and modifications. It was Jim Amos-Landgraf and Robert Plenge who studied patterns of skewed inactivation in different cohorts of females, either normal females23Plenge R.M. Hendrich B.D. Schwartz C. Arena J.F. Naumova A. Sapienza C. Winter R.M. Willard H.F. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation.Nat. Genet. 1997; 17: 353-356Crossref PubMed Scopus (217) Google Scholar, 24Amos-Landgraf J.M. Cottle A. Plenge R.M. Friez M. Schwartz C.E. Longshore J. Willard H.F. X chromosome inactivation patterns of 1005 phenotypically unaffected females.Am. J. Hum. Genet. 2006; 79: 493-499Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar or carriers of various X-linked clinical conditions.25Plenge R.M. Stevenson R.A. Lubs H.A. Schwartz C.E. Willard H.F. Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders.Am. J. Hum. Genet. 2002; 71: 168-173Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar It was Brian Chadwick and Cory Valley who began to explore chromatin aspects of X inactivation,26Chadwick B.P. Willard H.F. Chromatin of the Barr body: histone and non-histone proteins associated with or excluded from the inactive X chromosome.Hum. Mol. Genet. 2003; 12: 2167-2178Crossref PubMed Scopus (97) Google Scholar, 27Chadwick B.P. Willard H.F. Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome.Proc. Natl. Acad. Sci. USA. 2004; 101: 17450-17455Crossref PubMed Scopus (179) Google Scholar, 28Valley C.M. Pertz L.M. Balakumaran B.S. Willard H.F. Chromosome-wide, allele-specific analysis of the histone code on the human X chromosome.Hum. Mol. Genet. 2006; 15: 2335-2347Crossref PubMed Scopus (24) Google Scholar projects that continue in the lab today. Figure 5 illustrates the striking banding pattern of heterochromatin on the inactive X, which looks so reminiscent of the DNA replication timing patterns that Sam Latt and I had seen some 25 years before. Here, we're looking not at DNA replication timing, but rather chromatin variants and histone modifications on the inactive X, bringing nearly full circle the notion that the X chromosome—and by extension the whole genome—must be organized in a way that reflects a very careful interplay between the underlying sequence and the behavior, at a very large scale, of those sequences in the context of chromatin and the chromosome. The answer to that question is a life's pursuit and remains very much unfinished business. So, to me, the storyline shown in Figure 4 is a very straightforward one, reflecting a series of what seemed at the time to be logical and linear connections that have emerged in the decades since that day in October 1973. To you, you might be saying, “This was a plan?” But such is the nature of discovery science in human genetics (and certainly in human cytogenetics), in which so many roads, whatever the nature of the original motivation or insight, now seem to lead to genome sequence and to genome biology. But I haven't told you quite the whole story. If I go back to the very early days, when we were beginning to look at DNA sequences on the X in the late 1970s, it wasn't so much to clone genes that escaped from or were subject to inactivation. Rather, my initial hypothesis, when I was a postdoc working at Johns Hopkins with Kirby Smith and Barbara Schmeckpeper, was to identify an X-specific repeated DNA element that I thought, based on X inactivation models in the literature and based on the success that Lou Kunkel had had earlier in identifying tandemly repeated DNA from the Y chromosome,29Kunkel L.M. Smith K.D. Boyer S.H. Human Y-chromosome-specific reiterated DNA.Science. 1976; 191: 1189-1190Crossref PubMed Scopus (54) Google Scholar would be blocks of X inactivation elements distributed along the chromosome,30Schmeckpeper B.J. Willard H.F. Smith K.D. Isolation and characterization of cloned human DNA fragments carrying reiterated sequences common to both autosomes and the X chromosome.Nucleic Acids Res. 1981; 9: 1853-1872Crossref PubMed Scopus (30) Google Scholar similar to what has been hypothesized by Gartler and Riggs31Gartler S.M. Riggs A.D. Mammalian X-chromosome inactivation.Annu. Rev. Genet. 1983; 17: 155-190Crossref PubMed Scopus (461) Google Scholar as “way stations” or “booster elements” that could perpetuate the X inactivation signal up and down the length of the chromosome. And what a fine hypothesis that was! Other than, of course, the small fact that it seemed to be wrong… My efforts as a postdoc to identify X-specific repeating DNAs involved in X inactivation turned out to be a failed experiment of sorts, designed initially as an experiment to study X inactivation that turned out to be anything but that. The reality was that what I isolated was X-specific centromeric DNA, which, once we realized it,32Willard H.F. Smith K.D. Sutherland J. Isolation and characterization of a major tandem repeat family from the human X chromosome.Nucleic Acids Res. 1983; 11: 2017-2033Crossref PubMed Scopus (225) Google Scholar opened up a totally different side of the laboratory, a side that has allowed us to bridge back and forth for the past 25 years between two very different aspects of chromosome structure and function, one closely tied to gene expression, the other closely tied to chromosome biology. Having identified centromeric DNA allowed us, in experiments championed initially by John Waye, to explore alpha satellite DNA33Waye J.S. Willard H.F. Chromosome-specific alpha satellite DNA: Nucleotide sequence analysis of the 2.0 kilobasepair repeat from the human X chromosome.Nucleic Acids Res. 1985; 12: 2731-2743Crossref Scopus (164) Google Scholar (a then recently discovered but poorly understood DNA family in the human genome), which took us into the study of a large number of chromosome-specific DNAs and their utilization, genomic mapping and the organization of those sequences, satellite DNA and repetitive DNA evolution, and finally centromere function, all of which came from my initial failed expe" @default.
• W2088495596 created "2016-06-24" @default.
• W2088495596 creator A5039407032 @default.
• W2088495596 date "2010-03-01" @default.
• W2088495596 modified "2023-09-28" @default.
• W2088495596 title "2009 William Allan Award Address: Life in The Sandbox: Unfinished Business" @default.
• W2088495596 cites W1529475329 @default.
• W2088495596 cites W1582044099 @default.
• W2088495596 cites W1624539334 @default.
• W2088495596 cites W1779859408 @default.
• W2088495596 cites W1973445288 @default.
• W2088495596 cites W1991008526 @default.
• W2088495596 cites W1995303686 @default.
• W2088495596 cites W1996309079 @default.
• W2088495596 cites W2001841820 @default.
• W2088495596 cites W2014200281 @default.
• W2088495596 cites W2016078407 @default.
• W2088495596 cites W2018254240 @default.
• W2088495596 cites W2020958409 @default.
• W2088495596 cites W2029146706 @default.
• W2088495596 cites W2029920510 @default.
• W2088495596 cites W2031340189 @default.
• W2088495596 cites W2031351362 @default.
• W2088495596 cites W2032698359 @default.
• W2088495596 cites W2038794882 @default.
• W2088495596 cites W2041544429 @default.
• W2088495596 cites W2047333953 @default.
• W2088495596 cites W2066091852 @default.
• W2088495596 cites W2069644796 @default.
• W2088495596 cites W2072885333 @default.
• W2088495596 cites W2073223320 @default.
• W2088495596 cites W2077884141 @default.
• W2088495596 cites W2083410033 @default.
• W2088495596 cites W2086471138 @default.
• W2088495596 cites W2087424229 @default.
• W2088495596 cites W2089329246 @default.
• W2088495596 cites W2092787490 @default.
• W2088495596 cites W2093533550 @default.
• W2088495596 cites W2101235595 @default.
• W2088495596 cites W2101765976 @default.
• W2088495596 cites W2107959716 @default.
• W2088495596 cites W2112363223 @default.
• W2088495596 cites W2114033955 @default.
• W2088495596 cites W2115795607 @default.
• W2088495596 cites W2119468541 @default.
• W2088495596 cites W2121585267 @default.
• W2088495596 cites W2126084304 @default.
• W2088495596 cites W2164169825 @default.
• W2088495596 cites W2172046446 @default.
• W2088495596 cites W3024125022 @default.
• W2088495596 cites W4241390636 @default.
• W2088495596 cites W73840192 @default.
• W2088495596 doi "https://doi.org/10.1016/j.ajhg.2010.01.037" @default.
• W2088495596 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2833390" @default.
• W2088495596 hasPublicationYear "2010" @default.
• W2088495596 type Work @default.
• W2088495596 sameAs 2088495596 @default.
• W2088495596 citedByCount "1" @default.
• W2088495596 crossrefType "journal-article" @default.
• W2088495596 hasAuthorship W2088495596A5039407032 @default.
• W2088495596 hasBestOaLocation W20884955961 @default.
• W2088495596 hasConcept C138885662 @default.
• W2088495596 hasConcept C142362112 @default.
• W2088495596 hasConcept C161191863 @default.
• W2088495596 hasConcept C167981075 @default.
• W2088495596 hasConcept C41008148 @default.
• W2088495596 hasConcept C52119013 @default.
• W2088495596 hasConcept C86803240 @default.
• W2088495596 hasConcept C95124753 @default.
• W2088495596 hasConceptScore W2088495596C138885662 @default.
• W2088495596 hasConceptScore W2088495596C142362112 @default.
• W2088495596 hasConceptScore W2088495596C161191863 @default.
• W2088495596 hasConceptScore W2088495596C167981075 @default.
• W2088495596 hasConceptScore W2088495596C41008148 @default.
• W2088495596 hasConceptScore W2088495596C52119013 @default.
• W2088495596 hasConceptScore W2088495596C86803240 @default.
• W2088495596 hasConceptScore W2088495596C95124753 @default.
• W2088495596 hasIssue "3" @default.
• W2088495596 hasLocation W20884955961 @default.
• W2088495596 hasLocation W20884955962 @default.
• W2088495596 hasLocation W20884955963 @default.
• W2088495596 hasOpenAccess W2088495596 @default.
• W2088495596 hasPrimaryLocation W20884955961 @default.
• W2088495596 hasRelatedWork W163049555 @default.
• W2088495596 hasRelatedWork W169794994 @default.
• W2088495596 hasRelatedWork W1965401213 @default.
• W2088495596 hasRelatedWork W2078916040 @default.
• W2088495596 hasRelatedWork W2268712973 @default.
• W2088495596 hasRelatedWork W2682274646 @default.
• W2088495596 hasRelatedWork W2748952813 @default.
• W2088495596 hasRelatedWork W3193615524 @default.
• W2088495596 hasRelatedWork W394050644 @default.
• W2088495596 hasRelatedWork W612963211 @default.
• W2088495596 hasVolume "86" @default.
• W2088495596 isParatext "false" @default.
• W2088495596 isRetracted "false" @default.
• W2088495596 magId "2088495596" @default.
• W2088495596 workType "article" @default.