Sperm Production and More
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Page and Finnish geneticist Albert de la Chapelle embarked on their research in the early 1980s—not by studying typical XY men but rather by seeking out so-called sex-reversed individuals. XY women and XX men, individuals who appear to be one sex but have sex chromosomes of the opposite sex, provided clues to where the sex-determining gene might dwell on the Y chromosome. The tip-off was a snippet of Y attached to an X on the XX males as well as a segment of Y chromosome absent in the XY females. Page and de la Chapelle deduced that those bits of Y housed the critical gene. They produced an early map of the crucial area of where the sex-determining genes reside. The map would help researchers take the critical step in honing in on the exact address.
Page thought he had pinpointed the area on the Y itself and published his findings in 1987. But in 1990, a British team led by Peter Goodfellow nailed down the region, calling it SRY (short for sex-determining region Y). The protein produced by SRY may regulate other genes that cajole an embryo's fetal genital ridges into boyhood and prod the formation of testes. Once on the scene, the testes secrete hormones that instigate the male reproductive tract's development.
At puberty, sperm development and production, or spermatogenesis, are triggered within the seminiferous tubules in the testes by the hormone testosterone from the testes and gonadotropin hormones from the pituitary gland. Researchers wondered whether other genes on the Y chromosome orchestrated spermatogenesis. Again, the answers turned up in men who departed from the norm. In 1976, Y was first implicated in male infertility by Italian researchers who found deleted portions of the chromosome in men with spermatogenic failure. They labeled the region AZF, short for azoospermia factor. Two decades later, Page uncovered a chromosomal pattern in infertile men with azoospermia—an absence of sperm from semen, or oligozoospermia—a very low sperm count. In analyzing blood cells from these two groups, Page's team found that some men were missing a region of the Y chromosome, a deletion that was the same in each case. Later, Page's group found AZF deletions in the Y chromosomes of sperm isolated from men with oligozoospermia and evidence of AZF in blood cells. Within the AZF region, they discovered one gene with fertility connections, which they branded the DAZ gene (for deleted in azoospermia). DAZ is expressed only in the testes, where the gene is active in the very earliest stage of spermatogenesis. Last year, the group uncovered a mutation in USP9Y, a gene also within the AZF region, that results in infertility.
"One of the striking things is that at least half of the genes on the Y chromosome appear to be active in sperm production," Page says.
The discovery that gene mutations can cause infertility brought another question to the fore. Obviously, azoospermia is not inherited since men who produce no sperm cannot have children. Azoospermia shows up de novo in some males. But could men with oligozoospermia pass on the mutation to their sons? Researchers could not even approach this puzzle until 1992, when a revolutionary method of assisted reproduction enabled men with low sperm counts to father children, even if the oligozoospermia resulted from genetic defects. (Through intracytoplasmic sperm injection, or ICSI, physicians first retrieve sperm from the testicles or epididymis and then inject a single sperm into an egg.) By studying the fertility of sons conceived with ICSI, Page's group and researchers at the Infertility Center of St. Louis found that men with oligozoospermia do, in fact, produce sons likely to be infertile.
The inheritance of mutations other than those that cause infertility also captivates scientists who study the human male chromosome. For example, Page and his colleagues reported findings this summer in Nature concerning children with genetic diseases caused by a newly identified mutation. His group was interested in determining the proportion of new mutations that were inherited from fathers as opposed to mothers. Since the 1940s, biologists thought that the majority of new mutations came from the father. However, Page's lab found that the rates of inheritance between mothers and fathers are similar.
