The American Journal of Human Genetics, 24 July 2008
A Comparative Analysis of the Genetic Epidemiology of Deafness in the United States in Two Sets of Pedigrees Collected More than a Century Apart
Kathleen S. Arnos et al.
In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19th century. Each pedigree included three-generation data on marriage partners that included at least one deaf proband, who were ascertained by complete selection. We recently proposed that the intense phenotypic assortative mating among the deaf might have greatly accelerated the normally slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and the establishment of residential schools. Simulation studies suggest that this mechanism might have doubled the frequency of the commonest forms of recessive deafness (DFNB1) in this country during the past 200 years. To test this prediction, we collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay. Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children has increased by a factor of more than five in the past 100 years. Additional analysis within our sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920 through 1980). These data are consistent with the increase in the frequency of DFNB1 predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.
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The importance of heredity as a cause of hearing loss has been recognized at least since the beginning of the 19th Century. For example, in 1857, the Irish otologist William Wilde concluded from an analysis of questions about deaf individuals in census data that parental consanguinity and the existence of deafness in one or both parents were important indicators of a hereditary etiology in some cases.1 In 1883, Alexander Graham Bell published a report titled Memoir upon the Formation of a Deaf Variety of the Human Race, which included a retrospective analysis of records from schools for the deaf in the United States.2 Bell expressed his concern about “the formation of a deaf variety of the human race in America,” based on analyses of the frequency of deaf relatives of deaf students and the hearing status of the offspring of marriages among those who were congenitally deaf compared to those who were adventitiously deaf. Bell argued that the use of sign language, the trend toward education in residential schools, and the creation of societies and conventions for deaf people restricted mating choices and fostered intermarriage, leading to a steady increase in the frequency of congenital deafness. Geneticists have generally discounted Bell's concerns once the extreme heterogeneity of genes for deafness was recognized; however, as described below, recent evidence suggests that, in combination with relaxed selection, assortative mating among the deaf population might in fact have preferentially amplified the commonest forms of recessive deafness.3
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Because of the large number of recognized genes for deafness, the discovery that mutations at a single locus, DFNB1 (MIM 220290), account for 30%–40% of nonsyndromic deafness in many populations came as a great surprise. and  DFNB1 includes the GJB2 (MIM 121011) and GJB6 (MIM 604418) genes, coding for the Connexin 26 (Cx26) and Connexin 30 (Cx30) subunits of homologous gap-junction proteins. These subunits are expressed in the inner ear, where they form heteromeric gap-junction channels between adjacent cells that permit the exchange of small molecules and may facilitate the recycling of potassium ions from the hair cells, after acoustic stimulation, back into the cochlear endolymph. More than 154 GJB2 mutations have been identified in the coding exon of GJB2, but a single chain-termination mutation, 35 del G, accounts for up to 70% of pathologic alleles in many populations. Although DFNB1 is common in Western Europe and the Middle East, and  much lower frequencies have been observed in Asia.,  and  The 35 del G mutation exhibits linkage disequilibrium, and haplotype analysis suggests that it arose from a single individual in the Middle East approximately 10,000 years ago. and 20 M. Tekin, N. Akar, S. Cin, S.H. Blanton, X.J. Xia, X.Z. Liu, W.E. Nance and A. Pandya, Connexin 26 (GJB2) mutations in the Turkish population: implications for the origin and high frequency of the 35delG mutation in Caucasians, Hum. Genet. 108 (2001), pp. 385–389. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (27)
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In 2000, we proposed that the high frequency of DFNB1 deafness reflects the joint effect of intense assortative mating and the relaxed genetic selection against deafness, which occurred after the introduction of sign language 400 years ago in many Western countries and the subsequent establishment of residential schools for the deaf.29 Using computer simulation, we showed that this mechanism could have doubled the frequency of DFNB1 deafness in the United States during the past 200 years.3
Importance of the Mating Structure of the Population
Along with consanguinity, assortative mating is an important characteristic of a population that can have a profound influence on the incidence of deafness. When a new recessive mutation first arises, there is a substantial risk that it will be lost by stochastic processes. Consanguinity helps ensure that at least some recessive mutations are expressed phenotypically where they can be exposed to positive or negative selection. Only after genes for deafness are expressed can assortative mating accelerate their increase in response to relaxed selection. Consanguinity, of course, affects all recessive genes indiscriminately, but the effect of assortative mating among the deaf is limited to genes for deafness, in which it preferentially increases the frequency of the commonest form of recessive deafness in a population.3 Acting together, these genetic mechanisms can thus promote the survival, expression, and spread of genes for deafness. The acquisition of either a traditional or an indigenous sign language, especially when used by both deaf and hearing family members, is perhaps the most important factor that can improve the “genetic fitness” of the deaf population. Although their fitness was generally quite low in Europe prior to the time that sign language and schools for the deaf were introduced, it is now becoming apparent from a growing number of examples that a similar amplification of the frequency of specific genes for deafness can result from the development of indigenous sign languages that are used within extended families to allow deaf and hearing family members to communicate with one another., ,  and 33 T.B. Friedman, Y. Liang, J.L. Weber, J.T. Hinnant, T.D. Barber, S. Winata, I.N. Arhya and J.H. Asher, A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17, Nat. Genet. 9 (1995), pp. 86–91. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (94) As a result of the integration of the deaf population into the community, the fitness of deaf individuals can be unimpaired in this setting, and when D × D marriages occur, virtually all are noncomplementary, as expected, because there is usually only one form of genetic deafness in the community. Although gene drift and endogamy undoubtedly play essential roles in the survival and initial phenotypic expression of genes in such populations, it is hard to escape the conclusion that relaxed selection and assortative mating must also contribute to the remarkable increases that can be seen in both gene and phenotype frequencies and to the strong evidence for a founder effect.
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In the United States, 80%–90% of individuals with profound deafness currently marry a deaf partner;39 however, the introduction of cochlear-implant technology is profoundly altering the mating structure of the deaf population. By facilitating oral communication and educational mainstreaming, substantially all of the deaf children of hearing parents will be redirected into the hearing mating pool. Even if all of the deaf children of deaf parents eschewed implants, continued to learn sign language, and mated assortatively, the size of the pool would decrease dramatically and would be increasingly composed of individuals with DFNB1 mutations. Under these assumptions, the ultimate size at which the mating pool stabilizes might well be influenced by the extent to which genotypic mate selection replaces phenotypic selection in the interim (Nance et al., American College of Medical Genetics meeting 2006, San Diego, USA, Abstract 52). On the other hand, if deaf couples begin to embrace cochlear-implant technology for their children, the pool size will continue to decrease, eventually resulting in the substantial disappearance of the deaf culture. Thus, the collection and analysis of data on marriages of deaf individuals might represent a vanishing opportunity to understand the factors that have contributed to secular changes in the genetic epidemiology of deafness in this country since Fay's landmark study.