On Low Expectations Exceeded; or, The Genomic Salvation of the Y Chromosome**Previously presented at the annual meeting of The American Society of Human Genetics, in Los Angeles, on November 8, 2003.
2004; Elsevier BV; Volume: 74; Issue: 3 Linguagem: Inglês
10.1086/382659
ISSN1537-6605
Autores Tópico(s)Chromosomal and Genetic Variations
ResumoReceiving the Curt Stern Award makes me think of the year 1956, when Stern, an extraordinary Drosophila geneticist with broad-ranging interests, became president of the American Society of Human Genetics. It's also the year I was born. During the first year of my life, Stern presided over the Society's 10th annual meeting, in Ann Arbor. There, he delivered a presidential address entitled "On porcupine skin and hairy ears; or, the alleged sins of the Y chromosome." As usual, the editor of the American Journal of Human Genetics sanitized the title of Stern's address prior to publication ("The problem of complete Y-linkage in man" [Stern Stern, 1957Stern C The problem of complete Y-linkage in men.Am J Hum Genet. 1957; 9: 147-166PubMed Google Scholar]). In his presidential address, Stern debunked all 17 "presumably or possibly Y-linked traits"—all flimsy claims based on shoddy pedigree analysis. By the end of his speech, no genes were left standing on the human Y chromosome. Even today, pedigree analysis has yet to reveal a single Y-linked gene. Surely, it wasn't Stern's intention, but his entirely accurate pronouncement of the futility of Y-linked pedigree studies led others to a new understanding: the Y chromosome must be a genetic wasteland. And so began the Rodney Dangerfield era for the human Y chromosome. Rodney has always felt a special kinship with this chromosome, frequently declaring, "Y don't get no respect!" In truth, Curt Stern was a fervent supporter and student of the human Y chromosome. He simply lacked the molecular and genomic tools required to understand it. So let's invite Stern back to enjoy this occasion. First, for Stern's benefit, I would like to provide an executive summary of recent insights: Previously thought to be a genetic wasteland, the Y chromosome is now known to contain about 76 protein-coding genes. These genes collectively encode at least 27 distinct proteins. Many of these genes are functionally specialized in spermatogenesis (Lahn and Page Lahn and Page, 1997Lahn BT Page DC Functional coherence of the human Y chromosome.Science. 1997; 278: 675-680Crossref PubMed Scopus (687) Google Scholar; Skaletsky et al. Skaletsky et al., 2003Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.Nature. 2003; 423: 825-837Crossref PubMed Scopus (1487) Google Scholar).Today's X and Y chromosomes evolved from an ancestral pair of autosomes that existed 300 million years ago (Ohno Ohno, 1967Ohno S Sex chromosomes and sex-linked genes. Springer-Verlag, Berlin1967Crossref Google Scholar; Lahn and Page Lahn and Page, 1999Lahn BT Page DC Four evolutionary strata on the human X chromosome.Science. 1999; 286: 964-967Crossref PubMed Scopus (641) Google Scholar).Once considered to be merely a rotting copy of that ancient autosome, the Y chromosome is now understood to have expanded its gene repertoire during evolution through (1) selective importation of genes from autosomes and the X chromosome and (2) gene amplification (Saxena et al. Saxena et al., 1996Saxena R Brown LG Hawkins T Alagappan RK Skaletsky H Reeve MP Reijo R Rozen S Dinulos MB Disteche CM Page DC The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned.Nat Genet. 1996; 14: 292-299Crossref PubMed Scopus (373) Google Scholar; Skaletsky et al. Skaletsky et al., 2003Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.Nature. 2003; 423: 825-837Crossref PubMed Scopus (1487) Google Scholar).Although researchers had believed the Y chromosome was composed almost entirely of junky repeats (even in its euchromatic portions), it actually contains gene-rich palindromes of unprecedented scale and precision (Kuroda-Kawaguchi et al. Kuroda-Kawaguchi et al., 2001Kuroda-Kawaguchi T Skaletsky H Brown LG Minx PJ Cordum HS Waterston RH Wilson RK Silber S Oates R Rozen S Page DC The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men.Nat Genet. 2001; 29: 279-286Crossref PubMed Scopus (526) Google Scholar; Skaletsky et al. Skaletsky et al., 2003Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.Nature. 2003; 423: 825-837Crossref PubMed Scopus (1487) Google Scholar).We no longer think of the Y chromosome as a land of no recombination and, hence, of inevitable gene decay. We now understand it to be a place of abundant gene conversion. Researchers have speculated that gene conversion helps preserve the integrity of Y-chromosome genes across evolutionary time (Rozen et al. Rozen et al., 2003Rozen S Skaletsky H Marszalek JD Minx PJ Cordum HS Waterston RH Wilson RK Page DC Abundant gene conversion between arms of palindromes in human and ape Y chromosomes.Nature. 2003; 423: 873-876Crossref PubMed Scopus (416) Google Scholar; Skaletksy et al. Skaletsky et al., 2003Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.Nature. 2003; 423: 825-837Crossref PubMed Scopus (1487) Google Scholar). Curt, let me show you the heart of the Y chromosome—the AZFc region—a spectacular hall of mirrors. The region is dominated by near-perfect sequence reflections, including three massive palindromes (the largest spanning nearly 3 Mb) as well as other inverted and direct repeats (fig. 1A). But in this reflected beauty lies great danger—the hall of mirrors is fragile. Particularly treacherous are the direct repeats, revealed by horizontal lines in the triangular dot plot of fig. 1A. One pair of 229-kb direct repeats (amplicons b2 and b4 in fig. 1B) form irresistible targets for homologous recombination, yielding de novo deletions of the intervening 3.5 Mb of DNA at a frequency of 1 in 4,000 male births (Kuroda-Kawaguchi et al. Kuroda-Kawaguchi et al., 2001Kuroda-Kawaguchi T Skaletsky H Brown LG Minx PJ Cordum HS Waterston RH Wilson RK Silber S Oates R Rozen S Page DC The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men.Nat Genet. 2001; 29: 279-286Crossref PubMed Scopus (526) Google Scholar). Curt, as you speculated in your presidential address, the Y chromosome is loaded with fertility genes, and this is especially true in the AZFc region. Indeed, the recurrent b2/b4 (AZFc) deletion was the most common genetic cause of spermatogenic failure known—until this month, when Sjoerd Repping, Steve Rozen, and colleagues reported a far more common Y deletion, the gr/gr deletion (Repping et al. Repping et al., 2003Repping S Skaletsky H Brown K van Daalen SKM Korver CM Pyntikova T Kuroda-Kawaguchi T de Vries JWA Oates RD Silber S van der Veen F Page DC Rozen S Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection.Nat Genet. 2003; 35: 247-251Crossref PubMed Scopus (347) Google Scholar). The gr/gr deletion exists as a bona fide polymorphism in human populations, yet it tends to impair spermatogenesis. The gr/gr deletion removes half of the AZFc region (fig. 1C), reducing the copy number but not eliminating outright any of the region's testis-specific gene families; two of four DAZ genes remain. The gr/gr deletion can be identified in ∼1% of all men, making it perhaps 40 times as common as the b2/b4 (AZFc) deletion. Unlike the b2/b4 deletion, which almost always arises de novo, the gr/gr deletion is often inherited from the father. The gr/gr deletion increases the risk of spermatogenic failure, as demonstrated by association studies, but it does not routinely devastate spermatogenesis, as the b2/b4 (AZFc) deletion does. A true polymorphism, and a functionally important one at that, the gr/gr deletion represents the first meaningful convergence on the Y chromosome of medical genetics and population genetics (Repping et al. Repping et al., 2003Repping S Skaletsky H Brown K van Daalen SKM Korver CM Pyntikova T Kuroda-Kawaguchi T de Vries JWA Oates RD Silber S van der Veen F Page DC Rozen S Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection.Nat Genet. 2003; 35: 247-251Crossref PubMed Scopus (347) Google Scholar). We may come to think of the gr/gr deletion as the Y chromosome's ΔF508, or APOE4. Curt, in your presidential address, you also speculated that the human Y chromosome might have a role in sex determination, as was known in guppies and gypsy moths. You were right! In the developing human embryo, the gonad is the first structure to differentiate, anatomically, between XX and XY. Through work that began with Charles Ford (Ford et al. Ford et al., 1959Ford CE Miller OJ Polani PE de Almeida JC Briggs JH A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome).Lancet. 1959; 1: 711-713Abstract PubMed Scopus (517) Google Scholar) and Patricia Jacobs (Jacobs et al. Jacobs and Strong, 1959Jacobs PA Strong JA A case of human intersexuality having a possible XXY sex determining mechanism.Nature. 1959; 183: 302-303Crossref PubMed Scopus (550) Google Scholar) and culminated in the laboratories of Peter Goodfellow and Robin Lovell-Badge, we now know that a single gene on the Y chromosome—SRY—instructs the gonads to develop as testes (Sinclair et al. Sinclair et al., 1990Sinclair AH Berta P Palmer MS Hawkins JR Griffiths BL Smith MJ Foster JW Frischauf AM Lovell-Badge R Goodfellow PN A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif.Nature. 1990; 346: 240-244Crossref PubMed Scopus (2424) Google Scholar; Koopman et al. Koopman et al., 1991Koopman P Gubbay J Vivian N Goodfellow P Lovell-Badge R Male development of chromosomally female mice transgenic for Sry.Nature. 1991; 351: 117-121Crossref PubMed Scopus (1603) Google Scholar). Built around this knowledge is much additional genetic insight into the making of testes—and males. But here's the rub. Embarrassingly, in the year 2003, we know little genetically about the making of the ovary, about how an XX embryo begins to become a phenotypic female. We shamelessly legitimize our ignorance by referring to the female pathway as the "default." And so I pose a question for the future: what is the role of genes in the making of the ovary? I would like to offer an early observation that pertains to this question. Curt, we now think of genes not only as sites of heritable variation underlying phenotypes but also, through their RNA or protein products, as markers of cellular identity during development. My colleague Douglas Menke identified a gene, Stra8, whose expression pattern in embryonic gonads is intriguing in this light. Shown in figure 2 is the localization of Stra8 RNA in mouse gonads at 12.5–16.5 d after fertilization. Stra8 is expressed in XX (but not XY) embryonic gonads, in a slowly advancing wave that begins at ∼E12.5, near the anterior pole of the embryonic ovary, and ends at ∼E16.5, near the posterior pole. Other experiments have shown that Stra8 is expressed only in germ cells, not in the somatic cells of the gonad. At present, Stra8 expression in germ cells is the earliest known marker of female differentiation in mammals (Menke et al. Menke et al., 2003Menke DB Koubova J Page DC Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave.Dev Biol. 2003; 262: 303-312Crossref PubMed Scopus (259) Google Scholar). These findings raise the possibility that the first steps in turning an XX embryo into a phenotypic female may unfold in germ cells. Much work remains to be done! It is a delight to know that this vibrant community of scholars thinks well enough of my laboratory's work to honor me with the Curt Stern Award. At its best, science reflects not an individual effort, but a collective one, with a sense of mission and purpose shared among colleagues and shared between mentors and students. I am fortunate to have worked with an exceptional group of mentors, colleagues, and students throughout my career. I would like to express my appreciation to these men and women, too numerous to mention, whose creativity and perseverance are honored here today. Finally, and most especially, I'd like to remember the source of my own Y chromosome, a man who has been my greatest mentor and my greatest appreciator: Conrad Page, Jr. (September 20, 1920–October 17, 2003). The 2003 Curt Stern award is for you, Dad. I thank Laura Brown for assistance in preparing figures. My laboratory's work is supported by the National Institutes of Health and the Howard Hughes Medical Institute.
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