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Dive into the research topics where Huntington F. Willard is active.

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Featured researches published by Huntington F. Willard.


Nature Genetics | 1997

Formation of de novo centromeres and construction of first-generation human artificial microchromosomes.

John J. Harrington; Gil Van Bokkelen; Robert W. Mays; Karen Gustashaw; Huntington F. Willard

We have combined long synthetic arrays of alpha satellite DNA with telomeric DNA and genomic DNA to generate artificial chromosomes in human HT1080 cells. The resulting linear microchromosomes contain exogenous alpha satellite DNA, are mitotically and cytogenetically stable in the absence of selection for up to six months in culture, bind centromere proteins specific for active centromeres, and are estimated to be 6–10 megabases in size, approximately one-fifth to one-tenth the size of endogenous human chromosomes. We conclude that this strategy results in the formation of de novo centromere activity and that the microchromosomes so generated contain all of the sequence elements required for stable mitotic chromosome segregation and maintenance. This first-generation system for the construction of human artificial chromosomes should be suitable for dissecting the sequence requirements of human centromeres, as well as developing constructs useful for therapeutic applications.


Cell | 1990

Homologous ribosomal protein genes on the human X and Y chromosomes: Escape from X inactivation and possible implications for turner syndrome

Elizabeth M. C. Fisher; Peggy Beer-Romero; Laura G. Brown; Anne J. Ridley; John Mcneil; Jeanne B. Lawrence; Huntington F. Willard; Frederick R. Bieber; David C. Page

We have isolated two genes on the human sex chromosomes, one on the Y and one on the X, that appear to encode isoforms of ribosomal protein S4. These predicted RPS4Y and RPS4X proteins differ at 19 of 263 amino acids. Both genes are widely transcribed in human tissues, suggesting that the ribosomes of human males and females are structurally distinct. Transcription analysis revealed that, unlike most genes on the X chromosome, RPS4X is not dosage compensated. RPS4X maps to the long arm of the X chromosome (Xq), where no other genes are known to escape X inactivation. Curiously, RPS4X maps near the site from which the X-inactivating signal is thought to emanate. On the Y chromosome, RPS4Y maps to a 90 kb segment that has been implicated in Turner syndrome. We consider the possible role of RPS4 haploinsufficiency in the etiology of the Turner phenotype.


Science | 2010

Heritable Individual-Specific and Allele-Specific Chromatin Signatures in Humans

Ryan M. McDaniell; Bum Kyu Lee; Lingyun Song; Zheng Liu; Alan P. Boyle; Michael R. Erdos; Laura J. Scott; Mario A. Morken; Katerina S. Kucera; Anna Battenhouse; Damian Keefe; Francis S. Collins; Huntington F. Willard; Jason D. Lieb; Terrence S. Furey; Gregory E. Crawford; Vishwanath R. Iyer; Ewan Birney

Like Father, Like Mother, Like Child Transcriptional regulation is mediated by chromatin structure, which may affect the binding of transcription factors, but the extent of how individual-to-individual genetic variation affects such regulation is not well understood. Kasowski et al. (p. 232, published online 18 March) investigated the binding of two transcription factors across the genomes of human individuals and one chimpanzee. Transcription factor binding was associated with genomic features such as nucleotide variation, insertions and deletions, and copy number variation. Thus, genomic sequence variation affects transcription factor binding and may explain expression difference among individuals. McDaniell et al. (p. 235, published online 18 March) provide a genome-wide catalog of variation in chromatin and transcription factor binding in two parent-child trios of European and African ancestry. Up to 10% of active chromatin binding sites were specific to a set of individuals and were often inherited. Furthermore, variation in active chromatin sites showed heritable allele-specific correlation with variation in gene expression. An appreciable amount of variation in chromatin status and transcription factor binding has a genetic basis. The extent to which variation in chromatin structure and transcription factor binding may influence gene expression, and thus underlie or contribute to variation in phenotype, is unknown. To address this question, we cataloged both individual-to-individual variation and differences between homologous chromosomes within the same individual (allele-specific variation) in chromatin structure and transcription factor binding in lymphoblastoid cells derived from individuals of geographically diverse ancestry. Ten percent of active chromatin sites were individual-specific; a similar proportion were allele-specific. Both individual-specific and allele-specific sites were commonly transmitted from parent to child, which suggests that they are heritable features of the human genome. Our study shows that heritable chromatin status and transcription factor binding differ as a result of genetic variation and may underlie phenotypic variation in humans.


Trends in Genetics | 1990

Centromeres of mammalian chromosomes.

Huntington F. Willard

The centromere is the major cis-acting genetic locus involved in chromosome segregation in mitosis and meiosis. The mammalian centromere is characterized by large amounts of tandemly repeated satellite DNA and by a number of specific centromere proteins, at least one of which has been shown to interact directly with centromeric satellite DNA sequences. Although direct functional assays of chromosome segregation are still lacking, the data are most consistent with a structural and possibly functional role for satellite DNA in the mammalian centromere.


Molecular and Cellular Biology | 1987

Genomic organization of alpha satellite DNA on human chromosome 7: evidence for two distinct alphoid domains on a single chromosome.

J S Waye; S B England; Huntington F. Willard

A complete understanding of chromosomal disjunction during mitosis and meiosis in complex genomes such as the human genome awaits detailed characterization of both the molecular structure and genetic behavior of the centromeric regions of chromosomes. Such analyses in turn require knowledge of the organization and nature of DNA sequences associated with centromeres. The most prominent class of centromeric DNA sequences in the human genome is the alpha satellite family of tandemly repeated DNA, which is organized as distinct chromosomal subsets. Each subset is characterized by a particular multimeric higher-order repeat unit consisting of tandemly reiterated, diverged alpha satellite monomers of approximately 171 base pairs. The higher-order repeat units are themselves tandemly reiterated and represent the most recently amplified or fixed alphoid sequences. We present evidence that there are at least two independent domains of alpha satellite DNA on chromosome 7, each characterized by their own distinct higher-order repeat structure. We determined the complete nucleotide sequences of a 6-monomer higher-order repeat unit, which is present in approximately 500 copies per chromosome 7, as well as those of a less-abundant (approximately 10 copies) 16-monomer higher-order repeat unit. Sequence analysis indicated that these repeats are evolutionarily distinct. Genomic hybridization experiments established that each is maintained in relatively homogeneous tandem arrays with no detectable interspersion. We propose mechanisms by which multiple unrelated higher-order repeat domains may be formed and maintained within a single chromosomal subset.


PLOS Genetics | 2011

Analysis of dna methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation

Jason Gertz; Katherine E. Varley; Timothy E. Reddy; Kevin M. Bowling; Florencia Pauli; Stephanie L. Parker; Katerina S. Kucera; Huntington F. Willard; Richard M. Myers

The methylation of cytosines in CpG dinucleotides is essential for cellular differentiation and the progression of many cancers, and it plays an important role in gametic imprinting. To assess variation and inheritance of genome-wide patterns of DNA methylation simultaneously in humans, we applied reduced representation bisulfite sequencing (RRBS) to somatic DNA from six members of a three-generation family. We observed that 8.1% of heterozygous SNPs are associated with differential methylation in cis, which provides a robust signature for Mendelian transmission and relatedness. The vast majority of differential methylation between homologous chromosomes (>92%) occurs on a particular haplotype as opposed to being associated with the gender of the parent of origin, indicating that genotype affects DNA methylation of far more loci than does gametic imprinting. We found that 75% of genotype-dependent differential methylation events in the family are also seen in unrelated individuals and that overall genotype can explain 80% of the variation in DNA methylation. These events are under-represented in CpG islands, enriched in intergenic regions, and located in regions of low evolutionary conservation. Even though they are generally not in functionally constrained regions, 22% (twice as many as expected by chance) of genes harboring genotype-dependent DNA methylation exhibited allele-specific gene expression as measured by RNA-seq of a lymphoblastoid cell line, indicating that some of these events are associated with gene expression differences. Overall, our results demonstrate that the influence of genotype on patterns of DNA methylation is widespread in the genome and greatly exceeds the influence of imprinting on genome-wide methylation patterns.


American Journal of Human Genetics | 2006

X Chromosome–Inactivation Patterns of 1,005 Phenotypically Unaffected Females

James M. Amos-Landgraf; Amy Cottle; Robert M. Plenge; Mike Friez; Charles E. Schwartz; John W. Longshore; Huntington F. Willard

X-chromosome inactivation is widely believed to be random in early female development and to result in a mosaic distribution of cells, approximately half with the paternally derived X chromosome inactive and half with the maternally derived X chromosome inactive. Significant departures from such a random pattern are hallmarks of a variety of clinical states, including being carriers for severe X-linked diseases or X-chromosome cytogenetic abnormalities. To evaluate the significance of skewed patterns of X inactivation, we examined patterns of X inactivation in a population of >1,000 phenotypically unaffected females. The data demonstrate that only a very small proportion of unaffected females show significantly skewed inactivation, especially during the neonatal period. By comparison with this data set, the degree of skewed inactivation in a given individual can now be quantified and evaluated for its potential clinical significance.


The Lancet | 1985

PRENATAL-DIAGNOSIS AND CARRIER DETECTION OF DUCHENNE MUSCULAR-DYSTROPHY WITH CLOSELY LINKED RFLPS

E. Bakker; N Goor; K. Wrogemann; Louis M. Kunkel; W.A Fenton; D Majoor-Krakauer; M.G.J Jahoda; G.J.B. van Ommen; M. H. Hofker; Jean-Louis Mandel; Kay E. Davies; Huntington F. Willard; Lodewijk A. Sandkuyl; Anthonie J. van Essen; E.S Sachs; Peter L. Pearson

By the use of a series of closely linked DNA probes detecting restriction fragment length polymorphisms (RFLPs) distributed over the short arm of the X chromosome, a double crossover was detected in a Duchenne muscular dystrophy carrier and an affected male fetus was diagnosed at 12 weeks of gestation, with a probable accuracy of more than 99.0%. A new mutation was identified in another family with the same degree of reliability; three females in this family were thus deemed not to be DMD carriers. The eleven RFLP-markers presently available on the short arm of the X chromosome are useful in the diagnosis of DMD since they bridge the Duchenne locus at genetic distances varying between 3 and 20 cmo. Moreover, recombination within the set of markers provides an independent way of regionally mapping these probes relative to each other along the short arm of the X chromosome.


Cell | 1992

Integration of human α-satellite DNA into simian chromosomes: Centromere protein binding and disruption of normal chromosome segregation

Thomas Haaf; Peter E. Warburton; Huntington F. Willard

Centromeres of mammalian and other complex eukaryotic chromosomes are dominated by one or more classes of satellite DNA. To test the hypothesis that alpha-satellite DNA, the major centromeric satellite of primate chromosomes, is involved in centromere structure and/or function, human alpha-satellite DNA was introduced into African green monkey (AGM) cells. Centromere protein binding was apparent at the sites of integrated human alpha-satellite DNA. In the presence of an AGM centromere on the same chromosome, human alpha-satellite was associated with bridges between the separating sets of chromatids at anaphase and an increased number of lagging chromosomes at metaphase, both features consistent with the integrated alpha-satellite disrupting normal chromosome segregation. These experiments suggest that alpha-satellite DNA provides the primary sequence information for centromere protein binding and for at least some functional aspect(s) of a mammalian centromere, playing a role either in kinetochore formation or in sister chromatid apposition.


The New England Journal of Medicine | 1998

X INACTIVATION IN FEMALES WITH X-LINKED DISEASE

Jennifer M. Puck; Huntington F. Willard

X-linked recessive disorders affect males, whereas female carriers are generally spared. This is due in part to the random inactivation in females of one of the two X chromosomes in all somatic cel...

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Laura Carrel

Pennsylvania State University

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Carolyn J. Brown

University of British Columbia

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Andrew P. Miller

Case Western Reserve University

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Daynna J. Wolff

Case Western Reserve University

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Karen Gustashaw

Case Western Reserve University

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