In mammals and birds, sex differences in brain function and disease are thought to derive exclusively from sex differences in gonadal hormone secretions. For example, testosterone in male mammals acts during fetal and neonatal life to cause masculine neural development. However, male and female brain cells also differ in genetic sex; thus, sex chromosome genes acting within cells could contribute to sex differences in cell function. We analyzed the sexual phenotype of the brain of a rare gynandromorphic finch in which the right half of the brain was genetically male and the left half genetically female. The neural song circuit on the right had a more masculine phenotype than that on the left. Because both halves of the brain were exposed to a common gonadal hormone environment, the lateral differences indicate that the genetic sex of brain cells contributes to the process of sexual differentiation. Because both sides of the song circuit were more masculine than that of females, diffusible factors such as hormones of gonadal or neural origin also likely played a role in sexual differentiation.T heories of sexual differentiation in birds and mammals postulate different mechanisms for sexual differentiation of gonadal and nongonadal tissues (1). Gonadal sex is determined by sex chromosome gene(s). In mammals, the Y-linked SRY gene is expressed within cells in the undifferentiated gonadal ridge to induce testicular development (2). In contrast, sexual differentiation of nongonadal (somatic) tissues, such as the brain, is caused by sex differences in early gonadal hormones (3, 4). A key question is whether somatic sexual differentiation also involves cell-autonomous action of sex chromosome genes as occurs in gonadal differentiation.An exclusively hormonal theory of brain sexual differentiation has been challenged by studies of zebra finches (Taeniopygia guttata). Males, but not females, sing a courtship song. The male's neural song nuclei are much larger and have larger neurons (5). Treatment of hatchling females with estradiol induces more masculine neural development, and they sing (6), suggesting that estrogens derived from gonadal secretions normally induce masculine song system development in males. However, treatments with gonadal hormones do not completely sex-reverse females, and blocking testicular hormones in males does not prevent masculine development (1). Moreover, testicular tissue induced to develop in genetic females does not masculinize the song system (7). One explanation for these results is that sex chromosome genes are expressed differently within brain cells of the two sexes and act in a cell-autonomous fashion to cause differences in song system development (8).The discovery of a rare bilateral gynandromorphic zebra finch presented us with an opportunity to test this hypothesis, because cells on one half of its brain and body were genetically male and cells on the other half were genetically female. Because both halves of the brain developed in the same gonadal hormonal environment, a complete...

Rearrangements of chromosome 15q, including isodicentric 15 chromosomes and interstitial duplications and triplications, have been previously reported in association with autism spectrum disorders. We have identified two boys with exceptionally large der(15) chromosomes that are tricentric and contain four copies of the proximal long arm, including the Prader Willi/Angelman critical region, and leading to hexasomy of the involved segment. Biallelic inheritance of maternal alleles and methylation analysis indicate that the markers are maternally derived. Clinical assessment of the boys indicated severe cognitive impairment associated with marked delays in gross and fine motor skills. Social and language deficits were present in both, although the severity of the mental retardation precluded diagnosis of autism (both were considered to have pervasive developmental disorder-not otherwise specified). Neurologic manifestations included infantile spasms evolving into intractable early-onset myoclonic seizures, psychomotor regression, and profound diffuse hypotonia. These patients represent the most severe end of the spectrum of phenotypes associated with segmental aneuploidy for chromosome 15q11-q13.