David C. Page

Last updated
David Page
Born
David C. Page

1956 (age 6768)
NationalityAmerican
Alma mater
Awards
Scientific career
Fields Genetics
Institutions
Doctoral students Bruce Lahn
Website wi.mit.edu/people/faculty/page

David C. Page (born 1956) is an American biologist and professor at the Massachusetts Institute of Technology (MIT), the director of the Whitehead Institute, and a Howard Hughes Medical Institute (HHMI) investigator. [2] He is best known for his work on mapping the Y-chromosome and on its evolution in mammals and expression during development.

Contents

Education and early life

Page was born in Harrisburg, Pennsylvania, in 1956 and grew up in the rural outskirts of Pennsylvania Dutch country. [1] [3] [4] The first of his family to go to college, Page attended Swarthmore College, where he graduated with a BA with highest honors in chemistry in 1978. [3] [5] During his final year at Swarthmore, Page attended class just one day a week and spent the rest of his time researching chromatin structure in the laboratory of molecular biologist Robert Simpson at the National Institutes of Health. [3] [5] In 1978, Page enrolled at Harvard Medical School and the Harvard-MIT Health Sciences Program, where he worked in the laboratories of David Botstein at MIT and Raymond White at the University of Massachusetts Medical School. [5] In White's lab, Page worked on a project to develop a genetic linkage map of the human genome that would become a precursor to the Human Genome Project. [1] The work relied on locating restriction fragment length polymorphisms (RFLP). The first RFLP that Page found was from a site of homology between the X chromosome and Y chromosome, a coincidence that would set the direction of his subsequent career. [1]

Page finished his MD degree in the spring of 1984 and started his own lab as the first Whitehead Fellow at the Whitehead Institute for Biomedical Research researching the genetics of XX male syndrome, or de la Chapelle Syndrome. [1] [5] After Page won the MacArthur "Genius Grant" in 1986, Page was promoted to the faculty of the Whitehead Institute and the MIT Department of Biology in 1988. [5] [6] In 1990, Page was named a Howard Hughes Medical Institute Investigator, and in 2005 he was named as director of the Whitehead Institute. [5]

Research and career

Page has worked in several areas of genetics. [7] [8]

Mapping the Y chromosome

In his work on de la Chapelle Syndrome in 1986, Page collaborated with the geneticist who originally identified the first XX male, Albert de la Chapelle, and geneticist Jean Weissenbach to show that XX males carry a small piece of the Y chromosome. [1] [9] [10]

In the following year, he reported that the gene ZFY induced the development of the testes, a finding which received a great deal of media attention since it putatively resolving a decade-long search for the sex-determining gene. [1] [11] In 1989, a British team of scientists led by Peter Goodfellow and Robin Lovell-Badge began to report that the testis-determining gene was not ZFY, which led Page to review his data. Page found that he had misinterpreted his data because one of the XY females in his study had a second deletion at the site which proved to be the location of the real sex-determining gene. Launching a second round of media attention, Nature published his findings together with a paper from the British group that identified the sex-determining gene, which they termed SRY. [1] [11] [12]

Despite a belief among geneticists that the Y chromosome contained few genes other than the sex-determining gene, Page continued to map the Y chromosome. He had already published DNA-based deletion maps of the Y chromosome in 1986, [13] and went on to develop comprehensive clone-based physical maps of the chromosome in 1992 [14] [15] and systematic catalogs of Y-linked genes in 1997. [16] Page collaborated with a team at the Genome Institute at Washington University to make a complete map of the Y chromosome, which they achieved in 2003. [17] To do so, Page and his colleagues developed a new sequencing technique, single-haplotype iterative mapping and sequencing (SHIMS), since mammalian sex chromosomes contain too many repetitive sequences to be sequenced by conventional approaches. [3] The development of SHIMS allowed Page to identify long palindromic sequences on the long arm of the Y chromosome, which he would go on to show made the Y chromosome vulnerable to the deletions that cause spermatogenic failure (an inability to produce sperm). [18] In 2012, Page characterized the most common genetic cause of spermatogenic failure, the deletion of the AZFc region of the Y chromosome. [19] [20] The lab also found that aberrant crossing over within the Y chromosome's palindromes underlies a wide range of disorders of sexual differentiation, including Turner syndrome. [19]

Evolution of the Y chromosome

With the development of more detailed maps of the Y chromosome, in the mid-1990s Page began to find genetic evidence confirming the theory that both the X and Y chromosomes had evolved from autosomes, beginning with the 1996 discovery that a family of genes called DAZ (deleted in azoospermia) had been transposed from an autosome to the Y chromosome. [3] [21] In 1999, Page and his then-graduate student Bruce Lahn showed that the X and Y chromosomes had diverged in four steps, beginning 200-300 million years ago. [22] Later cross-species comparisons would show that while ancestral genes on the Y chromosome initially underwent rapid decay, [17] [23] the remaining genes have remained stable for the last 25 million years, [24] overturning the long-held view that the Y chromosome was going extinct. [3] In a 2014 study, Page concluded that the conserved genes on the Y chromosome played an important role in male viability, since they were dosage-dependent genes with similar but not identical counterparts on the X chromosome that all have regulatory roles in transcription, translation, and protein stability. Because these genes are expressed throughout the body, Page further concluded that these genes give rise to differences in the biochemistry of male and female tissues. [25]

In super-resolution studies of the sex chromosomes, Page has found evidence of an evolutionary "arms race" between the X and Y chromosomes for transmission to the next generation. In one study, Page found that human X and mouse Y chromosomes have converged, independently acquiring and amplifying gene families expressed in testicular germ cells. [26] Another study found that the mouse Y chromosome had acquired and massively amplified genes homologous to the testis-expressed gene families on the mouse X chromosome. [27]

The genetics of germ cells

Page used the mouse as a model to study the genetics of meiotic initiation, showing that retinoic acid (RA) is the key factor which induces meiosis, as well as identifying several important genes crucial to the meiotic initiation pathway, including Stra8 and DAZL. [28] [29] [30] Page further discovered that the differentiation germ cells into gametocytes (oocytes in females or spermatocytes in males) does not depend on meiotic initiation, as commonly thought, showing that germ cells deficient in Stra8, a gene that activates the meiotic pathway, are still capable of growth and differentiation. [31] [32]

Awards and honors

His honors and awards include:

Related Research Articles

<span class="mw-page-title-main">Meiosis</span> Cell division producing haploid gametes

Meiosis is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a zygote, a cell with two copies of each chromosome again.

<span class="mw-page-title-main">Y chromosome</span> Sex chromosome in the XY sex-determination system

The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining because it is the presence or absence of Y chromosome that determines the male or female sex of offspring produced in sexual reproduction. In mammals, the Y chromosome contains the SRY gene, which triggers development of male gonads. The Y chromosome is passed only from male parents to male offspring.

<span class="mw-page-title-main">X-inactivation</span> Inactivation of copies of X chromosome

X-inactivation is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome.

Meiotic drive is a type of intragenomic conflict, whereby one or more loci within a genome will affect a manipulation of the meiotic process in such a way as to favor the transmission of one or more alleles over another, regardless of its phenotypic expression. More simply, meiotic drive is when one copy of a gene is passed on to offspring more than the expected 50% of the time. According to Buckler et al., "Meiotic drive is the subversion of meiosis so that particular genes are preferentially transmitted to the progeny. Meiotic drive generally causes the preferential segregation of small regions of the genome".

The short-stature homeobox gene (SHOX), also known as short-stature-homeobox-containing gene, is a gene located on both the X and Y chromosomes, which is associated with short stature in humans if mutated or present in only one copy (haploinsufficiency).

<span class="mw-page-title-main">DAZL</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia-like is a protein that in humans is encoded by the DAZL gene.

cAMP responsive element modulator Protein-coding gene in the species Homo sapiens

cAMP responsive element modulator is a protein that in humans is encoded by the CREM gene, and it belongs to the cAMP-responsive element binding protein family. It has multiple isoforms, which act either as repressors or activators. CREB family is important for in regulating transcription in response to various stresses, metabolic and developmental signals. CREM transcription factors also play an important role in many physiological systems, such as cardiac function, circadian rhythms, locomotion and spermatogenesis.

<span class="mw-page-title-main">DAZ1</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia 1, also known as DAZ1, is a protein which in humans is encoded by the DAZ1 gene.

<span class="mw-page-title-main">USP9Y</span> Protein-coding gene in the species Homo sapiens

Ubiquitin specific peptidase 9, Y-linked , also known as USP9Y, is an enzyme which in humans is encoded by the USP9Y gene. It is required for sperm production. This enzyme is a member of the peptidase C19 family and is similar to ubiquitin-specific proteases, which cleave the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins.

<span class="mw-page-title-main">DAZ3</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia protein 3 is a protein that in humans is encoded by the DAZ3 gene.

<span class="mw-page-title-main">DAZ2</span> Protein-coding gene in the species Homo sapiens

Deleted in azoospermia protein 2 is a protein that in humans is encoded by the DAZ2 gene.

<span class="mw-page-title-main">ZFY</span> Protein-coding gene in the species Homo sapiens

Zinc finger Y-chromosomal protein is a protein that in humans is encoded by the ZFY gene of the Y chromosome.

<span class="mw-page-title-main">DMRT1</span> Protein-coding gene in humans

Doublesex and mab-3 related transcription factor 1, also known as DMRT1, is a protein which in humans is encoded by the DMRT1 gene.

<span class="mw-page-title-main">BOLL</span> Protein-coding gene in the species Homo sapiens

Protein boule-like is a protein that in humans is encoded by the BOLL gene.

<span class="mw-page-title-main">UTY (gene)</span> Protein-coding gene in the species Homo sapiens

Histone demethylase UTY is an enzyme that in humans is encoded by the UTY gene.

<span class="mw-page-title-main">MAK (gene)</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase MAK is an enzyme that in humans is encoded by the MAK gene.

<span class="mw-page-title-main">EIF1AY</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 1A, Y-chromosomal is a protein that in humans is encoded by the EIF1AY gene.

<span class="mw-page-title-main">PRDM9</span> Protein-coding gene in humans

PR domain zinc finger protein 9 is a protein that in humans is encoded by the PRDM9 gene. PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain. PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.

<span class="mw-page-title-main">STAG3 (gene)</span> Protein-coding gene in the species Homo sapiens

Stromal antigen 3 is a protein that in humans is encoded by the STAG3 gene. STAG3 protein is a component of a cohesin complex that regulates the separation of sister chromatids specifically during meiosis. STAG3 appears to be paramount in sister-chromatid cohesion throughout the meiotic process in human oocytes and spermatocytes.

X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells.

References

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