signed an informed-consent document describing SOAEs and the procedures used to measure them. Hearing was tested

Proc. Natl. Acad. Sci. USA Vol. 90, pp. 11900-11904, December 1993 Psychology A masculinizing effect on the auditory systems of human females having male co-twins (otoacoustic emissions/opposite-sex twins/intrauterne-position phenomenon) DENNIS MCFADDEN* Department of Psychology and The Institute for Neuroscience, The University of Texas, Austin, TX 78712 Communicated by Ira J. Hirsh, September 17, 1993 ABSTRACT Spontaneous otoacoustic emissions (SOAEs) are continuous, essentially tonal sounds that are produced by many normal-hearing cochleas. In humans, females generally exhibit more SOAEs than males, a sex difference that exists from birth. However, it is shown here that females having male co-twins [opposite-sex dizygotic (OSDZ) females] exhibit about half the average number of SOAEs per ear observed in same-sex female twins or female non-twins. Indeed, the average in OSDZ females is about the same as that seen in males-twins or non-twins. The explanation offered here is that prenatal exposure to high levels of androgens has produced a masculinizing effect on the auditory systems of these OSDZ females. Prenatal mascinizing effects have long been recognized in certain litter-bearing mammals, but their existence in humans is not well-studied. Normal development and sexual differentiation in mammals require appropriate prenatal exposures to various biochemical and hormonal stimuli at successive stages in the developmental process. In certain litter-bearing (polytocous) mammals, prenatal exposure of a genetic female to high levels of androgens will later cause that animal to appear masculinized on numerous physiological and behavioral characteristics (1). Such exposures occur naturally when a female fetus is, by chance, positioned between two male fetuses (the intrauterine-position phenomenon). Here it is demonstrated that the auditory systems of human females having male co-twins are, in at least one regard, more similar to those of males than to other females. This difference appears to be an example of a prenatal masculinization effect in humans. Spontaneous otoacoustic emissions (SOAEs) are continuous, essentially tonal sounds that are produced in the cochlea and propagate back through the middle ear into the external ear canal where they can be recorded using sensitive miniature microphone systems (2, 3). Typically, these sounds are weak [sound-pressure levels less than about 20 decibels (db) re 20,uPa] and are inaudible to their owners-presumably because the auditory nervous system comes to ignore this continuous, low-level stimulation. Thus, SOAEs are not ordinarily a source of tinnitus (4). SOAEs are one of a family of otoacoustic emissions that can be recorded in the external ear canal (for a review, see ref. 5), and, unlike the others, they are rarely found in species below the primates (6). SOAEs are present only in cochleas having normal hearing sensitivity (5) and are reversibly reduced or eliminated by such ototoxic drugs as aspirin and quinine (e.g., refs. 7 and 8). SOAEs are more common in females and right ears than in males or left ears (9, 10), and prevalence appears to be directly related to degree of skin pigmentation (11). SOAEs are observed in infants (12), where the sex and ear differences in SOAE The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. 1734 solely to indicate this fact. 11900 expression are already established. The existing evidence suggests that SOAEs are highly stable through life (5). SOAEs serve no known function themselves and are probably best thought of as an epiphenomenon, as is discussed below. Knowledge of both the differential prevalence ofsoaes in the two sexes in humans and the intrauterine-position phenomenon in polytocous mammals led to the conjecture that the prenatal environment of those human females having male co-twins might render them less likely than other females to exhibit SOAEs. Accordingly, opposite-sex dizygotic (OSDZ) twins were added to an ongoing study on the heritability of SOAEs (13). METHODS Subjects were recruited through contact letters sent to University of Texas students having the same last name and birthdate, notices and announcements in large undergraduate classes, and advertising in local city and high school newspapers. Data were collected only after a subject had read and signed an informed-consent document describing SOAEs and the procedures used to measure them. Hearing was tested using a screening audiometer (Maico MA40), and all subjects independently completed a personal-facts inventory and questionnaire. Twins were categorized as monozygotic (MZ) or dizygotic on the basis of the similarity in their responses to some of the items on the questionnaire. The questions and two-level scoring system of Nichols and Bilbro (14) were used to determine zygosity, with one exception. When the second-level rules did not produce an unambiguous categorization for a set of twins, no "intuitive judgment" was made, but instead the data from those subjects were discarded. Nichols and Bilbro argued that this questionnaire procedure identifies the zygosity of twins with an accuracy >90%. Two subjects were tested at a time. They lay on small camp cots located in different soundproofed rooms. A small pillow supported the electrical leads coming from the microphone probe assembly inserted in the external ear canal. No data were collected until the subjects had been in position for at least 15 min. For each recording system, the output of an Etymotic low-noise microphone was preamplified, high-pass filtered at 400 Hz (to remove noise due to breathing and gross bodily movements), amplified, and delivered to a Nicolet/ Wavetek 444a Mini-Ubiquitous spectrum analyzer. The analyzer summed eight consecutive "samples" (fast Fourier transforms) for both the 2-kHz and 5-kHz low-pass ranges for each ear studied. These fast Fourier transforms were stored Abbreviations: SOAE, spontaneous otoacoustic emission; OSDZ, opposite-sex dizygotic; SSDZ, same-sex dizygotic; MZ, monozygotic. *To whom reprint requests should be addressed at: Department of Psychology, Mezes Hall 330, The University of Texas, Austin, TX 78712.

Psychology: McFadden as data files for later analysis. The data files were searched for spectral peaks (SOAEs) using an objective algorithm that successively compared the outputs of a sliding wide-band window (60 or 150 Hz wide for the 2- and 5-kHz ranges, respectively) with a sliding narrow-band window (20 or 50 Hz wide) centered within it. Any positive difference of 2 db or more was defined as an SOAE. The identification of SOAEs was done by the author, while still ignorant of the zygosity of the subjects. Not included in the presentation and analyses below are the data for a number of subjects who were discarded for various reasons. To be included in the data analysis, a subject had to be within 20 db of normal hearing for the test frequencies 1.0-4.0 khz, inclusive. Two sets of MZs, two sets of OSDZs, one male OSDZ, and two male non-twins were discarded for hearing loss. One set of twins and two non-twins were discarded because of technical or equipment problems. Five sets oftwins were lost because zygosity could not be unambiguously determined using the Nichols and Bilbro procedures (14). Surely the most important exclusion was an OSDZ female who was discarded as an outlier because her 6 SOAEs in each ear put her 7.8 SDs above the mean of the rest of her group. The outlier's co-twin had 3 SOAEs in each ear, which put him 2.48 SDs above the mean of his group (he was not excluded). The excluded OSDZ female also has female twin siblings who are 2 years younger and are probably same-sex dizygotics (SSDZs); one has 15 SOAEs and the other 8. Their data were among those lost because the zygosity-determining scheme employed (14) could not categorize them unambiguously. Thus, there appear to be factors at work in this family to produce tendencies toward both multiple births and an abundance of SOAEs. A remote possibility is that the excluded OSDZ female began life with an identical twin who vanished (15); her total of 12 SOAEs puts her "only" 1.3 SDs above the mean of the female MZs. RESULTS The outcome of primary interest here is that OSDZ females had fewer SOAEs than any other group of females, and they were comparable to males on this measure. This fact is illustrated in Fig. 1, where the mean number of SOAEs per 3.0 F Proc. Natl. Acad. Sci. USA 90 (1993) 11901 ear is shown for each subject group. The data are shown in more detail in Tables 1 and 2. In Table 1 the subjects are cross-classified by zygosity, sex, and category of SOAE expression; the mean age of each group is indicated at the bottom. In Table 2 the number (and proportion) of SOAEs in the two ears is shown. Means of two sorts are presented in Table 2; the total number of SOAEs in a group was divided both by the total number of ears in the group (mean per ear) and by only the number of ears having at least one SOAE (mean per emitting ear). It is the former that are shown in Fig. 1. Examination of the means per emitting ear reveals that, in addition to OSDZ females having fewer SOAEs overall than other females, those female OSDZ ears that did have SOAEs had fewer than other female ears. Note that the sex difference and ear asymmetry in SOAEs are evident both in the mean SOAEs per ear and in the proportions of subjects in the various SOAE categories, while the masculinization effect on OSDZ females appears only in the means. [More detailed presentations and analyses of other aspects of these data will appear in a paper concerned with the heritability of SOAEs (D.M. and J. C. Loehlin, unpublished data).] To confirm statistically that OSDZ females have fewer SOAEs than other females, the most appropriate, and statistically most powerful, comparison is between SSDZ and OSDZ females (both did have co-twins-they were just of different sex). When the mean numbers of SOAEs per ear were compared for these two groups, the result was statistically significant [t(31) = 1.99, P = 0.0275, one-tailed test]. Since the number of SOAEs in corresponding ears of SSDZ co-twins was correlated (intraclass correlation coefficient of about 0.2), the independence assumption would be violated by analyzing all 32 SSDZ females as individual subjects. Instead, for this t test, a four-ear average was used to characterize eachpair of SSDZs; the same statistical decision is reached when a two-ear average for a single co-twin chosen at random is used. If the data for the OSDZ female who was excluded as an outlier were included in Table 2, the mean number of SOAEs per ear and the mean per emitting ear would become 0.97 and 1.94, respectively, for OSDZ females. Thus, with this subject included, the pattern of the data is unchanged, but the statistical analysis does fail to reach significance [t(32) = 0.85, P = 0.20, one-tailed test]. Alternatively, significance is Q) Cla U) CD) 0 Co ~0 E z a) Ca a, 2.0 1.0 0.0 Monozygotics Same-Sex Non - Twins Opposite-Sex Dizygotics Dizygotics FIG. 1. Mean number of SOAEs per ear in each of the subject groups tested. The numerical bases for these means appear in Table 2. Of primary interest here is how dissimilar OSDZ females are from all other females.

11902 Psychology: McFadden Proc. Natl. Acad. Sci. USA 90 (1993) Table 1. Numbers (and proportions) of subjects of differing types having no SOAEs, SOAEs in one ear only, or SOAEs in both ears MZs SSDZs Non-twins OSDZs Parameter 9 d All 9 6 All 9 U All 9 U All SOAEs None 13 20 33 9 15 24 14 18 32 7 10 17 (0.28) (0.59) (0.41) (0.28) (0.63) (0.43) (0.37) (0.53) (0.44) (0.41) (0.59) (0.50) Left ear only 1 0 1 3 1 4 2 2 4 2 0 2 (0.02) (0.00) (0.01) (0.09) (0.04) (0.07) (0.05) (0.06) (0.06) (0.12) (0.00) (0.06) Rightear only 6 5 11 5 4 9 7 7 14 2 4 6 (0.13) (0.15) (0.14) (0.16) (0.17) (0.16) (0.18) (0.21) (0.19) (0.12) (0.24) (0.18) Both ears 26 9 35 15 4 19 15 7 22 6 3 9 (0.57) (0.26) (0.44) (0.47) (0.17) (0.34) (0.39) (0.21) (0.31) (0.35) (0.18) (0.26) Total subjects 46 34 80 32 24 56 38 34 72 17 17 34 Mean age, years 21.4 21.1 21.3 19.4 17.8 18.7 24.6 24.3 24.5 21.7 19.8 20.8 The numbers in parentheses are the proportions of subjects. achieved with the outlier included if a double square-root transform is performed prior to analysis. [All analyses were implemented using SYSTAT (16).] Had the 3 SOAEs in each ear of the outlier's co-twin been excluded, the mean SOAEs per ear and mean SOAEs per emitting ear for OSDZ males would be 0.41 and 1.63, respectively. DISCUSSION Various earlier findings were confirmed by the present data. For example, there were more SOAEs in females and right ears than in males and left ears (9). Also, while it is not shown in this presentation, there was a tendency for dark-eyed subjects to be more likely to exhibit SOAEs than light-eyed subjects (ref. 11; D.M. and J. C. Loehlin, unpublished data). Perhaps the most striking feature of the data in Table 2 is that MZ females had far more SOAEs than the other groups of subjects, and, again, this effect was greater in the dark-eyed subjects. The details of the evidence for heritability of SOAEs will be presented elsewhere (D.M. and J. C. Loehlin, unpublished data), but it should be noted that the number of SOAEs in corresponding ears of MZ co-twins was more highly correlated (intraclass correlation coefficient of about 0.8) than in other types of twins or in non-twins paired pseudorandomly (those correlation coefficients ranged from about -0.1 to +0.3)-a finding that suggests SOAE expression contains a heritable component (refs. 13 and 17; D.M. and J. C. Loehlin, unpublished data). It is important to emphasize that while we tested primarily young adults, there is good reason to believe that similar results would be obtained from other age groups. No longitudinal study of SOAEs in large groups of subjects yet exists, but strong SOAEs are observed in infants (12, 18), and the SOAEs in a number of individual ears have proved to be remarkably constant ever since their discovery about 15 years ago (5). The current weight of evidence suggests that SOAEs can be lost during a lifetime (as hearing is lost), but probably few, if any, are gained (ref. 5; for an exception see ref. 19). Thus, it seems reasonable to view SOAEs as a relatively stable characteristic of a person's phenotype. It is still unknown whether OSDZ females are born having fewer SOAEs than other females, but it seems reasonable to believe they are since the sex difference in SOAE prevalence does exist in infants (12). From past and present results, the following account of SOAEs emerges: (i) In its default (female) state, the human auditory system apparently has a relatively strong tendency to exhibit SOAEs, but the process of producing a male seemingly operates to offset that tendency. In accord with this premise is the generally higher prevalence of SOAEs in females (9) and the reduced prevalence in OSDZ females. (ii) OSDZ females exhibit fewer SOAEs than other females. A parsimonious interpretation is that the prenatal presence of a male co-twin has led to a masculinization of the cochleas of OSDZ females on some dimensions that are related to the later expression of SOAEs. In litter-bearing mammals, prenatal masculinizing of genetically female fetuses has been attributed to their exposure to high levels of androgens diffusing from adjacent male fetuses (1). Boklage (20) has previously argued that both male and female fetuses develop differently when gestated with an opposite-sex cotwin. (iii) MZ twins, especially MZ females, exhibit more SOAEs than other people of the same sex (see Fig. 1). This circumstance could occur in either of two ways. Either (option 1) there is something about the process of MZ twinning and/or development that causes an increase in the number of potential SOAEs in the cochleas of MZ twins relative to other people, or (option 2) some or all embryos begin gestation with the potential to exhibit quite large numbers of SOAEs and these potential SOAEs are ordinarily pared back by a succession of developmental processes (including masculinization), but, for some reason, one or Table 2. Numbers (and proportions) of SOAEs in the two ears of the different types of-subjects MZs SSDZs Non-twins OSDZs SOAEs 9 a All 9 6 All 9 U All 9 6 All Left ears 92 26 118 36 7 43 40 15 55 9 7 16 (0.40) (0.46) (0.41) (0.41) (0.37) (0.41) (0.33) (0.33) (0.33) (0.39) (0.37) (0.38) Right ears 137 31 168 51 12 63 83 31 114 14 12 26 (0.60) (0.54) (0.59) (0.59) (0.63) (0.59) (0.67) (0.67) (0.67) (0.61) (0.63) (0.62) Total SOAEs 229 57 286 87 19 106 123 46 169 23 19 42 Mean SOAEs per ear 2.49 0.84 1.79 1.36 0.40 0.95 1.62 0.68 1.17 0.68 0.56 0.62 SD* 2.68 1.34 2.35 1.65 0.64 1.39 2.04 1.08 1.71 0.68 0.98 0.84 Mean SOAEs per emitting ear 3.88 2.48 3.49 2.29 1.46 2.08 3.15 2.00 2.73 1.44 1.90 1.62 The numbers in parentheses are the proportions of SOAEs. *SDs for mean per ear values in the preceding row.

Psychology: McFadden more of these paring processes acts less effectively in MZ females than in other fetuses. Current evidence prevents a firm conclusion about these alternative possibilities. (iv) The higher prevalence of SOAEs in dark-skinned or dark-eyed people (ref. 11; D.M. and J. C. Loehlin, unpublished data) suggests a connection between pigmentation and the expression of SOAEs. The auditory system and all pigmented cells have a common embryological origin in the cells of the neural crest, a number of auditory anomalies are often accompanied by anomalies of pigmentation, and several auditory characteristics are thought to covary with eye color and/or skin pigmentation (21-24). These facts suggest that embryological events associated with the differentiation of neural crest cells may be responsible for creating SOAEs. The neural crest begins to emerge at about weeks 3-4 postconception (25). Since male fetal testosterone levels peak during weeks 11-17 of fetal age and then decline to values indistinguishable from those seen in female fetuses (26), it is tempting to presume that whatever process makes males so devoid of SOAEs occurs in this time period. By this reasoning, the auditory systems of female OSDZ twins may be affected by their male co-twins primarily during weeks 11-17 of fetal development. For comparison it can be noted that by week 10 postconception the embryonic human cochlea has achieved its full 2.5 turns, and scala tympani and scala vestibuli have been formed, although it is not until the fifth month that adult dimensions are attained and the eighth month that functional maturity is achieved (see refs. 27 and 28 for reviews). Inner and outer hair cells are first identifiable about week 22. Although it is not central to the matters of primary interest here, it is worth noting that the vast majority of MZ twins have become separate embryos long before the neural crest emerges. By one estimate, about one-third of all MZ twins have divided into separate embryos before day 5 postconception, about two-thirds between days 5 and 10, and only about 4% later than days 10-14 (29). Thus, it seems unlikely that the MZ twinning process itself is responsible for the abundance of SOAEs exhibited by MZ females (option 1 above) because twinning per se greatly predates both the emergence of the neural crest and the existence of an embryonic cochlea. While the exact effect on the auditory systems of the female OSDZ twins is unknown, a speculation can be offered. Since increased levels of activity in the medial olivocochlear system produce reductions in otoacoustic emissions of various sorts (e.g., refs. 30 and 31), one guess is that the strength of this efferent influence is in some way increased in OSDZ females relative to other females. Recently, the parallel sex differences and ear asymmetries seen for SOAEs and hearing sensitivity were similarly speculated to be due to differential strength of the efferent supply to individual cochleas (10). If these speculations were correct, it would complicate the rather simple story suggested above in that the efferent system does not develop until quite late in the prenatal period (27, 28), which seemingly requires that the crucial events underlying the prenatal masculinization effect occur later than weeks 11-17 of fetal life, when androgen levels are at their peak (26). Four predictions emerge from the prenatal-masculinization explanation offered here. The first is that a male having a male co-twin might have fewer SOAEs than a male having no co-twin-on the presumption that androgen concentration in the intrauterine fluid would be somewhat higher in the former case than the latter. The data in Fig. 1 offer a partial confirmation of this prediction. SSDZ males did have fewer SOAEs than non-twin males (or OSDZ males), although the difference was not statistically significant. However, MZ males did not have fewer SOAEs than non-twin males. This Proc. Natl. Acad. Sci. USA 90 (1993) 11903 fact appears to support the possibility that potential SOAEs are somehow actively added in MZ twins (option 1 above). The second prediction pertains to birth order. In rodents, the general flow of intrauterine fluids is from the fallopian tubes toward the cervix (32). If the flow of intrauterine fluids is similar in humans, fewer SOAEs might be expected in female fetuses in position to be born early than in those positioned to be born late. However, when the female OSDZ data were examined by birth order, the direction of effect was opposite to the prediction. The mean number of SOAEs per ear was 0.78 and 0.43 for first-born and second-born OSDZ females, respectively. Further, the proportion of first-born OSDZ females having at least one SOAE was 0.67 versus the 0.43 of the second-born females. Of course, relative intrauterine position early in gestation may be poorly related to ultimate birth order in human twins. The third prediction is that, as a group, OSDZ females should have hearing that is a few decibels less sensitive than that of other females. This stems from the widely accepted presumption that the presence of otoacoustic emissions is emblematic of superior hearing sensitivity (5, 33). Verification of this prediction would require precise psychophysical testing, not the simple audiometric screening that was employed here. The fourth prediction involves those genetic males whose androgen receptors were abnormal or deficient during prenatal development and who consequently exhibit female morphology (called testicular feminization). The prenatalmasculinization explanation suggests that these people will exhibit more SOAEs than other genetic males. No attempt has been made to test this prediction. It is unlikely that there has been evolutionary pressure to produce SOAEs per se. Rather, they are probably best thought of as an epiphenomenon of mechanisms that surely were under evolutionary pressure-namely, some aspect(s) of cochlear structure or development that are crucial to our ability to hear weak sounds. Mammalian ears contain a fragile, metabolically dependent mechanism, commonly called the cochlear amplifler (34), that is necessary for the detection of the weakest sounds heard by normal ears. Loss of the cochlear amplifier through exposure to intense sounds or certain ototoxic drugs leads to a hearing loss of up to 40 db in the frequency regions affected. As noted, SOAEs are found only in those frequency regions demonstrating normal hearing, thus suggesting a strong link between SOAEs and an intact cochlear amplifier. In passing, it should be noted that the masculinization of females having male co-twins further argues that the sex and ear differences that exist in the expression of SOAEs (9) are not the result of cochlear pathology (e.g., ref. 35), perhaps induced by differential exposure to intense sounds (19, 36). It is important to emphasize that-while no attempt was made to objectify this fact-the OSDZ females did not differ noticeably in appearance, stature, carriage, or behavior from the other females tested. If there are consequences of their prenatal overexposure to androgens beyond those on the auditory system, they are not apparent to casual examination. The masculinization effects observed in litter-bearing mammals are also subtle (1). The only other physiological demonstration known to me of a masculinizing effect in human OSDZ females involves dental asymmetries (20). There is also a report that females with male co-twins scored higher than non-twin females on a scale of sensation-seeking (37), but it is possible for experiential factors to have contributed to that outcome. The study of additional characteristics of OSDZ twins in general, and OSDZ females in particular, is encouraged, for it offers the potential to reveal both specific and general information about normal development and sexual differentiation in humans.

11904 Psychology: McFadden I am deeply grateful to G. L. Dykstra, R. Mishra, J. G. Sirianni, E. G. Pasanen, S. D. Casto, and N. L. Callaway for their conscientious work collecting data and recruiting subjects. J. C. Loehlin and F. S. vom Saal made many helpful comments on a preliminary draft. This work also profited from conversations with W. S. Geisler, R. K. Young, J. H. Langlois, E. M. Miller, and J. M. Horn. This work was supported by Grant DC 00153 from the National Institute on Deafness and Other Communication Disorders (NIDCD). 1. vom Saal, F. S. (1989) J. Anim. Sci. 67, 1824-1840. 2. Kemp, D. T. (1978) J. Acoust. Soc. Am. 64, 1386-1391. 3. Kemp, D. T. (1979) Arch. Otorhinolaryngol. 224, 37-45. 4. McFadden, D. & Wightman, F. L. (1983) Annu. Rev. Psychol. 34, 95-128. 5. Probst, R., Lonsbury-Martin, B. L. & Martin, G. K. (1991) J. Acoust. Soc. Am. 89, 2027-2067. 6. Lonsbury-Martin, B. L. & Martin, G. K. (1988) Hear. Res. 34, 313-317. 7. McFadden, D. & Plattsmier, H. S. (1984) J. Acoust. Soc. Am. 76, 443-448. 8. McFadden, D. & Pasanen, E. G. (1991) J. Acoust. Soc. Am. 90, Pt. 2, 2289 (abstr.). 9. Bilger, R. C., Matthies, M. L., Hammel, D. R. & Demorest, M. E. (1990) J. Speech Hear. Res. 33, 418-432. 10. McFadden, D. (1993) Hear. Res. 68, 143-151. 11. Whitehead, M. L., Kamal, N., Lonsbury-Martin, B. L. & Martin, G. K. (1993) Scand. Audiol. 22, 3-10. 12. Burns, E. M., Arehart, K. H. & Campbell, S. L. (1992) J. Acoust. Soc. Am. 91, 1571-1575. 13. Sirianni, J. G., McFadden, D. & Dykstra, G. L. (1992) Asha 34, 170 (abstr.). 14. Nichols, R. C. & Bilbro, W. C., Jr. (1966) Acta Genet. (Basel) 16, 265-275. 15. Landy, H. J., Keith, L. & Keith, D. (1982) Acta Genet. Med. Gemellol. 31, 179-194. 16. SYSTAT, Inc. (1992) SYSTAT: Statistics, Version 5.2 Edition (SYSTAT, Evanston, IL). Proc. Natl. Acad. Sci. USA 90 (1993) 17. Russell, A. F. & Bilger, R. C. (1992) J. Acoust. Soc. Am. 92, Pt. 2, 2409 (abstr.). 18. Norton, S. J. (1992) J. Acoust. Soc. Am. 91, Pt. 2, 2409 (abstr.). 19. Zurek, P. M. & Clark, W. W. (1981) J. Acoust. Soc. Am. 70, 446-450. 20. Boklage, C. E. (1985) Am. J. Hum. Genet. 37, 591-605. 21. Waardenburg, P. J. (1951) Am. J. Hum. Genet. 3, 195-253. 22. Brown, K. S. (1973) J. Acoust. Soc. Am. 54, 569-575. 23. Creel, D., Garber, S. R., King, R. A. & Witkop, C. J., Jr. (1980) Science 209, 1253-1255. 24. Cable, J., Barkway, C. & Steel, K. P. (1992) Hear. Res. 64, 6-20. 25. Kandel, E. R. & Schwartz, J. H. (1985) Principles of Neural Science (Elsevier, New York), 2nd Ed., pp. 245, 730. 26. Reyes, F. I., Boroditsky, R. S., Winter, J. S. D. & Faiman, C. (1974) J. Clin. Endocrinol. Metab. 38, 612-617. 27. Hecox, K. (1975) in Infant Perception: From Sensation to Cognition. Vol II. Perception ofspace, Speech and Sound, eds. Cohen, L. B. & Salapatek, P. (Academic, New York), pp. 151-191. 28. Walsh, E. J. & McGee, J. (1986) in Neurobiology ofhearing: The Cochlea, eds. Altschuler, R. A., Hoffman, D. W. & Bobbin, R. P. (Raven, New York), pp. 247-269. 29. Bulmer, M. G. (1970) The Biology of Twinning in Man (Clarendon Press, Oxford), p. 33. 30. Mountain, D. C. (1980) Science 210, 71-72. 31. Mott, J. B., Norton, S. J., Neely, S. T. & Warr, W. B. (1989) Hear. Res. 38, 229-242. 32. Even, M. D., Dhar, M. G. & vom Saal, F. S. (1992)J. Reprod. Fertil. 96, 709-716. 33. McFadden, D. & Mishra, R. (1993) Hear. Res., in press. 34. Davis, H. (1983) Hear. Res. 9, 79-90. 35. Ruggero, M. A., Rich, N. C. & Freyman, R. (1983) Hear. Res. 10, 283-300. 36. Clark, W. W., Kim, D. O., Zurek, P. M. & Bohne, B. A. (1984) Hear. Res. 16, 299-314. 37. Resnick, S. M., Gottesman, I. I. & McGue, M. (1993) Behav. Genet. 23, 323-329.