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Common Molecular Etiologies Are Rare in Nonsyndromic Tibetan Chinese Patients with Hearing Impairment

  • Yongyi Yuan ,

    Contributed equally to this work with: Yongyi Yuan, Xun Zhang

    Affiliations Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China, Department of Otolaryngology, Hainan Branch of PLA General Hospital, Sanya, People's Republic of China

  • Xun Zhang ,

    Contributed equally to this work with: Yongyi Yuan, Xun Zhang

    Affiliation Department of Otolaryngology, 3rd hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China

  • Shasha Huang,

    Affiliation Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China

  • Lujie Zuo,

    Affiliations Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China, Department of Otolaryngology, 3rd hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China

  • Guozheng Zhang,

    Affiliations Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China, Department of Otolaryngology, 3rd hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China

  • Yueshuai Song,

    Affiliation Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China

  • Guojian Wang,

    Affiliations Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China, Department of Otolaryngology, Hainan Branch of PLA General Hospital, Sanya, People's Republic of China

  • Hongtian Wang,

    Affiliation Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China

  • Deliang Huang ,

    daipu301@vip.sina.com (PD); hdy301@263.net (D. Han); huangdl301@sina.com (D. Huang)

    Affiliation Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China

  • Dongyi Han ,

    daipu301@vip.sina.com (PD); hdy301@263.net (D. Han); huangdl301@sina.com (D. Huang)

    Affiliation Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China

  • Pu Dai

    daipu301@vip.sina.com (PD); hdy301@263.net (D. Han); huangdl301@sina.com (D. Huang)

    Affiliations Department of Otolaryngology, PLA General Hospital, Beijing, People's Republic of China, Department of Otolaryngology, Hainan Branch of PLA General Hospital, Sanya, People's Republic of China

Common Molecular Etiologies Are Rare in Nonsyndromic Tibetan Chinese Patients with Hearing Impairment

  • Yongyi Yuan, 
  • Xun Zhang, 
  • Shasha Huang, 
  • Lujie Zuo, 
  • Guozheng Zhang, 
  • Yueshuai Song, 
  • Guojian Wang, 
  • Hongtian Wang, 
  • Deliang Huang, 
  • Dongyi Han
PLOS
x

Abstract

Background

Thirty thousand infants are born every year with congenital hearing impairment in mainland China. Racial and regional factors are important in clinical diagnosis of genetic deafness. However, molecular etiology of hearing impairment in the Tibetan Chinese population living in the Tibetan Plateau has not been investigated. To provide appropriate genetic testing and counseling to Tibetan families, we investigated molecular etiology of nonsyndromic deafness in this population.

Methods

A total of 114 unrelated deaf Tibetan children from the Tibet Autonomous Region were enrolled. Five prominent deafness-related genes, GJB2, SLC26A4, GJB6, POU3F4, and mtDNA 12S rRNA, were analyzed. Inner ear development was evaluated by temporal CT. A total of 106 Tibetan hearing normal individuals were included as genetic controls. For radiological comparison, 120 patients, mainly of Han ethnicity, with sensorineural hearing loss were analyzed by temporal CT.

Results

None of the Tibetan patients carried diallelic GJB2 or SLC26A4 mutations. Two patients with a history of aminoglycoside usage carried homogeneous mtDNA 12S rRNA A1555G mutation. Two controls were homozygous for 12S rRNA A1555G. There were no mutations in GJB6 or POU3F4. A diagnosis of inner ear malformation was made in 20.18% of the Tibetan patients and 21.67% of the Han deaf group. Enlarged vestibular aqueduct, the most common inner ear deformity, was not found in theTibetan patients, but was seen in 18.33% of the Han patients. Common molecular etiologies, GJB2 and SLC26A4 mutations, were rare in the Tibetan Chinese deaf population.

Conclusion

The mutation spectrum of hearing loss differs significantly between Chinese Tibetan patients and Han patients. The incidence of inner ear malformation in Tibetans is almost as high as that in Han deaf patients, but the types of malformation vary greatly. Hypoxia and special environment in plateau may be one cause of developmental inner ear deformity in this population.

Introduction

Hereditary hearing loss is a genetically heterogeneous disorder in humans, with an incidence rate of approximately 1 in 1000 children [1]. Nonsyndromic deafness accounts for 60–70% of inherited hearing impairment cases and involves 114 loci and 66 different genes with autosomal dominant (DFNA), autosomal recessive (DNFB), X-linked (DFN), and maternal inheritance patterns [2].

In China, there are 27.80 million people with hearing and speech disabilities; of these, 20.04 million have simple hearing disability [3], with genetic factors accounting for about 55% of the Chinese deaf population of Han ethnicity [3][4]. Worldwide, the most common causes of nonsyndromic autosomal recessive hearing loss are mutations in connexin 26, a gap-junction protein encoded by the GJB2 gene [5][13]. Defects in SLC26A4, which encodes the anion (chloride/iodide, chloride/bicarbonate) transporter Pendrin, can cause nonsyndromic DFNB4 deafness with enlargement of the vestibular aqueduct (EVA) and Pendred syndrome [14], [15]. A mutation of SLC26A4 mutation is the second most common cause of deafness in China [4]. Although the majority of cases of hereditary hearing loss are caused by nuclear gene defects, it has become clear that mutations in mitochondrial DNA (mtDNA) can also cause nonsyndromic hearing loss. The best studied mutations related to aminoglycoside suscepterblity are A1555G and C1494T in the mitochondrial 12S rRNA gene [16][18]. Nonsyndromic inherited hearing impairment caused by mutations in GJB2, SLC26A4, or mtDNA 12S rRNA typical accounts for 33.8% of the cases of deafness in areas of China [4].

China is a multiethnic country. Tibetans live mainly on the Tibetan Plateau, an area of southwest China with an average altitude of 4000 m above sea level, making it one of the highest region in the world. High-altitude hypoxia (reduced inspired oxygen tension owing to decreased barometric pressure) exerts severe physiological stress on the human body. Populations living on the Tibetan Plateau exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude, and these responses have been well characterized physiologically. Recent studies of the genetics associated with high-altitude adaptation have facilitated the genotype–phenotype studies necessary to confirm the role of selection-determined candidate genes and gene regions involved in adaptation to altitude [19], [20]. Although hearing and vestibular disorders at high altitude have been reported since 1938, the etiologies of these disorders are still unknown. The mechanisms by which the auditory system adapts to high altitude have not been elucidated in detail, and the molecular etiology of hereditary hearing loss in populations on the Tibetan Plateau remains unknown.

In the present study, we comprehensively analyzed five prominent deafness-related genes, i.e., GJB2, SLC26A4, mtDNA 12S rRNA, GJB6, and POU3F4, in 114 Tibetan patients from unrelated families in the Tibetan Plateau who experienced early-onset, nonsyndromic hearing impairment, to investigate the molecular etiology of hereditary hearing loss in this region. All of the patients underwent temporal computed tomography (CT) to evaluate inner ear development. In addition, detailed genotype and phenotype analyses were performed in the Tibetan hearing loss patients.

Materials and Methods

Patients and DNA samples

A total of 114 Tibetan deaf subjects from unrelated families were included in this study. They were all from Lhasa Special Education School, which is the only special education school in Tibet Autonomous Region. This cohort consisted of 57 males and 57 females ranging in age from 8 to 21 years, with an average age of 12.10±2.75 years. The study protocol was approved by the ethics committee of the Chinese PLA General Hospital. Written informed consent was obtained from all subjects or their parents prior to blood sampling. Parents were interviewed with regard to age at onset, family history, mother's health during pregnancy, and patient's clinical history, including infection, possible head or brain injury, and the use of aminoglycoside antibiotics.

All subjects showed moderate to profound bilateral sensorineural hearing impairment on audiograms. Careful medical examinations revealed no clinical features other than hearing impairment. None of the Tibetan patients with hearing impairment in our study showed any sign of vestibular dysfunction in their case history. Using a commercially available DNA extraction kit (Watson Biotechnologies Inc., Shanghai, China), DNA was extracted from the peripheral blood leukocytes of the 114 patients with nonsyndromic hearing loss and the 106 region- and ethnicity-matched controls with normal hearing.

Mutational analysis

For all patients, the GJB2 coding region plus approximately 50 bp of the flanking intron regions and the mitochondrial 12S rRNA gene (nt611 to nt2007) were amplified by PCR, followed by sequence analysis using the Big Dye sequencing protocol with an ABI 3100 Genetic Analyzer and analysis software v.3.7 NT (Applied Biosystems, Foster City, CA), according to the manufacturer's protocol. Patients with a monoallelic GJB2 coding region mutation were further tested for the GJB2 IVS1+1G>A mutation or defects in exon 1 and the promoter of GJB2. The specific promoter region of GJB2 includes 128 bp.The basal promoter,exon 1 and donor splice site of GJB2 gene can be found in GenBank (accession number U43932.1); the GJB6 309-kb deletion; and the mutations of the entire GJB6 coding region. The presence of the 309-kb GJB6 deletion was analyzed by PCR [15], [16]. A positive control (provided by Balin Wu, Department of Laboratory Medicine, Children's Hospital Boston and Harvard Medical School, Boston, MA) was used to detect GJB6 gene deletions.

The exons of SLC26A4 of all 114 patients were sequenced individually, starting with the frequently mutated exons, until two mutant alleles were identified. The patients verified with an inner ear malformation on a temporal bone CT scan were further tested for a POU3F4 gene mutation.

Similarly, the GJB2, SLC26A4, and mtDNA 12S rRNA genes from 106 Tibetan controls with normal hearing were sequenced to determine the presence of mutations and exon variants. As no POU3F4 variants, with the exception of two silent mutations, were found in the individuals with hearing loss, POU3F4 was not sequenced in the control group.

CT scan

All 114 patients were examined by temporal bone CT for diagnosis of EVA or other inner ear malformations, at the General Hospital of Tibet Military District. The diagnosis of EVA was based on a diameter of >1.5 mm at the midpoint between the common crus and the external aperture. For radiological comparison, the temporal CT results in 120 patients, mainly of Han ethnicity, with sensorineural hearing loss were analyzed at the Genetic Testing Center for Deafness of PLA General Hospital.

Results

Among the 114 cases included in this study, 88 had prelingual hearing loss, including 56 cases of congenital hearing loss. Eight cases showed postlingual hearing loss, with an average age of onset of 2.97±1.37 years. The age of onset was unclear in the remaining 18 cases. Thirteen cases (8 prelingual and 5 postlingual), with an average age of onset of 2.01±1.18 years, had a clear history of aminoglycoside administration. Patients with no history of aminoglycoside usage showed a significantly earlier average age of onset (0.92±1.03 years; P<0.001).

GJB2 gene mutations

Sequence analysis of the GJB2 gene indicated that none of the Tibetan patients carried two pathogenic mutations. Only two Tibetan patients carried a confirmed GJB2 heterozygous pathogenic mutation, c.235delC and c.299_300delAT mutation, respectively (Table 1). One Han patient carried a heterozygous c.235delC mutation.

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Table 1. Genotypes of GJB2 gene in Tibetan patients with hearing loss and Tibetan controls.

https://doi.org/10.1371/journal.pone.0030720.t001

The allele frequency of p.R127H, classified as a pathogenic GJB2 mutation, was significantly higher in the patient group than in the control group (P<0.05), indicating that p.R127H may be a mutation in the Chinese Tibetan hearing loss population. However, all 15 patients with the p.R127H mutation were heterozygotes. The pathogenic GJB2 mutation p.R32H was carried by a control subject, but was not found in the patients. An unclassified variant, p.T123N, had been counted as a mutation in a previous Japanese study, but as a polymorphism in studies performed in Taiwan and Turkey [12], [21], [22]. We found two p.T123N alleles in our Tibetan control subjects, but none in the Tibetan patient group (P>0.05), suggesting that it may be a neutral variant. The frequency of p.V37I was higher in the deaf group than in the controls in the present study, but the difference was not significant (P>0.05). The p.V37I variant was considered a pathogenic mutation in Japanese, Iranian, Korean, Moroccan, Malay, Israeli, Australian, and Italian studies [12], [23][30], but was reported as a variant in African-American, Caribbean Hispanic, French, Chinese, and Thai individuals with hearing impairment [31][34]. There was no significant difference in the allele frequency of p.V153I, classified previously as a polymorphism [2], between the Tibetan patient group and the controls in the present study (P>0.05), and we regarded it as a polymorphism. The p.V27I, p.E114G, and p.I203T variants were polymorphisms in the Chinese populations of Han [13] and Tibetan ethnicity. The GJB2 IVS1+1G to A mutation was not detected in patients with a heterozygous GJB2 mutation, and no novel nucleotide alterations were identified in the Tibetan hearing loss patients or control subjects.

SLC26A4 gene mutations

Six nucleotide changes in the SLC26A4 gene were verified through sequencing of all 20 exons of the gene from 114 Tibetan patients (Table 2). None of the Tibetan patients carried an SLC26A4 mutation on two alleles. Four patients exhibited the heterozygous c.1826T>G (p.V609G) variant. In addition, four c.1826T>G heterozygotes were verified in the control group. As there was no significant difference between the patient and control groups, we considered this a polymorphism in the Tibetan population, although Pryor et al. classified it as a mutation in 2005 [2]. The IVS13+9 C>T variant was first reported as a splice site mutation by Yong et al. in 2001 [35]. The IVS13+9 C>T variant was carried by one patient in the heterozygous state in our study population, and it did not predict a gain or loss of a splice site when analyzed using the Neural Network Splice Site Prediction Tool NNSPLICE0.9 (available at http://www.fruitfly.org/seq_tools/splice.html). Therefore, we considered this to be a benign variant.

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Table 2. Genotypes and phenotype of SLC26A4 gene in Tibetan patients with hearing loss.

https://doi.org/10.1371/journal.pone.0030720.t002

Two patients carried novel unclassified missense variants of SLC26A4, c.757A>G (p.I253V) and c.1522A>G (p.T508A), respectively. We found four p.I253V heterozygotes, but no p.T508A carriers in the control group. The frequency of p.I253V was higher in the control group than in the patient group (P>0.05). No p.I253V allele was found in 100 normally hearing individuals of Han ethnicity (unpublished data). Thus, we considered it to be a polymorphism typical of the Tibetan Chinese population.

Both c.273A>T (p.G91G) and c.753C>T (p.L251L) are silent variants of SLC26A4. The intron18-56delCAAA was considered to be an intron variant.

MtDNA 12S rRNA gene mutations

Two Tibetan patients and two normal hearing Tibetan controls carried a homogeneous mtDNA 12S rRNA A1555G mutation. Neither the C1494T mutation nor any other 12S rRNA mutation associated with hearing impairment, including nucleotide changes at positions 961 and 1095, were found in the Tibetan patient or control groups.

POU3F4 mutations

No POU3F4 mutations, with the exception of the two polymorphisms 708A>G (E236E) and 710G>C (E236E), were identified in the 23 patients with inner ear malformation.

Temporal bone CT scan

Nine types of inner ear malformations were verified on temporal bone CT scans in 23 Tibetan patients (a total of 37 ears) (Table 3). The frequency of inner ear malformation in the Tibetan hearing-loss patients was 20.18% (23/114). EVA, the most common type of inner ear malformation in China reported in previous studies, was not detected in the Tibetan deafness patients in the present study. The results of temporal CT in 120 patients, mainly of Han ethnicity, with sensorineural hearing loss revealed that 21.67% (26/120) had an inner ear malformation, 18.33% (22/120) had EVA, and only 3.33% (4/120) showed other types of inner ear malformations, including hypoplastic cochlea, hypoplastic vestibular aqueduct, incomplete partition type I, and common cavity (Fig. 1).

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Figure 1. CT images of inner ear malformation in Tibetan patients with hearing impairment.

a. incomplete partition type I b. common cavity deforrmity c. malformation of inner ears including cochlea,vestibular and semicircular canals d. malformation of cochlea and enlargement of internal auditory canals e. narrow internal auditory canal f. malformation of vestibular and semicircular canals g. malformation of semicircular canals h. malformation of cochlea i. ossification of the inner ear.

https://doi.org/10.1371/journal.pone.0030720.g001

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Table 3. Temporal bone CT Scan Phenotype in Chinese Tibetan patients with hearing loss.

https://doi.org/10.1371/journal.pone.0030720.t003

Discussion

According to the second nationwide survey of the disabled Chinese population performed in 2006, there were 27.80 million people with hearing and speech disabilities in China. The number of Chinese with hearing disability alone is 20.04 million, representing 1.54% of the population (20.04 million/1300 million). The percentage of the population with hearing disability in the Tibet Autonomous Region is 1.65% [36]. More than 92% of the whole population in the Tibet Autonomous Region is Tibetan, and 93.4% of the patients in our study population were Tibetan. Despite a similar incidence of moderate to profound sensorineural hearing loss in the Tibetan and Chinese populations, the molecular etiology in Tibetan patients appeared differ markedly from that in the Chinese population as a whole based on the present results. We found no homozygous or compound heterozygous mutations of the GJB2 or SLC26A4 gene. The mtDNA 12S rRNA A1555G homogeneous mutation and the use of aminoglycoside antibiotics were responsible for hearing loss in 1.75% (2/114) of the Tibetan patients. In typical areas of China, GJB2 gene mutations account for the etiology in about 18.31% of patients with hearing loss, SLC26A4 mutations account for about 13.73%, and the 12S rRNA A1555G mutation accounts for 1.76% [4]. There is no significant difference in the 12S rRNA A1555G mutation rate between the Tibetan patients with hearing impairment and the patients mainly of Han ethnicity.

The pathogenicity of the GJB2 p.V37I mutation is controversial. In a multicenter study, p.V37I was shown to be associated with mild to moderate hearing impairment (median, 25–40 dB) [37]. Our recent study indicated p.V37I had an allele frequency of 6.7% (185/2744) in a Han patient group (excluding all cases with two clearly pathogenic mutations), and this was significantly higher than that in a control population (2.8%, 17/602; P = 0.0003) [13], supporting Wu's suggestion that p.V37I should be reassigned from an allele variant to a pathogenic mutation [38]. In the present study, the frequency of p.V37I was higher in Tibetan patients with hearing loss than in ethnicity-matched controls, but the difference was not significant (P>0.05). Since our sample size was still too small to reach a confident statistical conclusion.and only two of our Tibetan patients carried GJB2 p.V37I (table 1), our results didn't support that p.V37I was pathogenic in Tibetan Chinese patients. Alternative explanation may be another unknown mutation associated with the V37I mutation is responsible for the etiology of Tibetan Chinese patients with hearing loss.

POU3F4 has been identified only for the Locus DFN3. The clinical features of DFN3 often include mixed progressive hearing loss, temporal bone anomalies, and stapes fixation [39][41]. POU3F4 belongs to a subfamily of transcription factors characterized by two conserved DNA-binding domains, a POU and a HOX domain, containing a helix-turn-helix structural DNA-binding motif. Several reports have described POU3F4 mutations in patients with hearing loss and temporal bone abnormalities [42]. Temporal bone CT scans of DFN3 patients as well as the Pou3f4 knockout inner ear phenotypes have suggested that most of the inner ear malformations were in structures derived from the mesenchyme [43], [44]. However, no variants or mutations were found in Tibetan patients recruited in this study with inner ear malformation.A series of transcription factors, including Pax2, Six, Eya1, Dlx, Hmx2–3, GATA3, RA, Otx1–2, IGF-1, and Tbx1, are related to the development of the mammalian otic capsule, and defects in these factors were reported to cause inner ear deformities in mice [45][54]. As the phenotype and genotype correlations for these genes in human patients with inner ear malformation are not clear, we did not screen for these genes in our patients.

The inner ear malformations in our Tibetan patients were diverse and severe. EVA, the most common inner ear deformity, was not found in our cases. This radiological finding was consistent with the genetic analyses, as no diallelic mutations were found in the open reading frame of SLC26A4. A novel SLC26A4 variant, p.T508A, was identified in the Tibetan patient group. The location of this amino acid in an evolutionarily conserved region implies that its substitution may result in a structurally and/or functionally different protein. We then carried a SIFT analysis on SLC26A4 p.T508A variant.The SIFT score was 0.17 and the SIFT prediction result was that the amino acid change was tolerated,which indicated it may be only a variant or be less likely a pathogenic mutation.There are two types of inner ear malformation: osseous labyrinth deformity and membranous labyrinth deformity. We assessed only the osseous labyrinth shape by high-resolution temporal bone CT. Magnetic resonance imaging (MRI) and water image of the inner ear may be valuable for assessment of membranous labyrinth deformity. However, we did not perform these two radiological examinations and could not evaluate the membranous labyrinth. Whether malformation of vestibular and/or semicircular canals can cause hearing-related phenotypes is not certain, but imbalances of the ion environment in the cochlea as well as structural abnormalities can result in hearing impairment. Hearing loss caused by EVA is an example of a pathology with normal cochlear structure, but with a suggested cochlear ion imbalance.

To our knowledge, there have been no previous studies of the genetic etiology of hearing loss in Tibetan patients. The distinct mutational spectrum of common hearing-related genes in the Tibetan patients compared with typical patients in other areas of China may be explained by ethnic and regional factors. According to archeological data, the Tibetan Plateau was first populated approximately 25,000 years ago. Compared with low-altitude populations, the populations indigenous to the high-altitude zones possess unique physiological characteristics [55]. Some of the environmental hardships at high altitudes include, but are not limited to, decreased ambient oxygen tension, increased solar radiation, extreme diurnal ranges in temperature, arid climate, and poor soil quality. The incidence of congenital heart disease including patent ductus arteriosus,ventricular septal defect,ventricular septal defect, atrial septal defect and valvular insufficiency in the Tibetan plateau is 0.615%.It is higher than that in lower altitude areas in China,which is 0.31% in Chengdu from Sichuang Province, 0.239% in Hefei from Anhui Province and 0.28% in Fuzhou from Fujian Province,respectively [56]. And with the increase of altitude in the same province,the incidence of congenital heart disease is increasing,which indicated that anoxia in high altitude area was regarded as one of the enviromental factors related with congenital heart disease [57]. Several studies have shown that Tibetan populations have lower hemoglobin concentrations than lowland Chinese populations [58]. Related studies have explored the heritability of specific altitude-related phenotypes, such as arterial oxygen saturation and hemoglobin concentration [58][60]. One heritability study concluded that there is a major autosomal dominant locus for high oxygen saturation, and Tibetan women carrying this high oxygen-saturation allele had higher offspring survival than those with a low oxygen-saturation allele [59]. In addition, positively selected haplotypes of EGLN1 and PPARA were significantly associated with the decreased hemoglobin phenotype unique to this highland population [20]. The genetic evidence for high-altitude adaptation in Tibet suggests that epigenetic regulation may play a greater role in the physiopathological process in Tibetans, although this has yet to be confirmed. High-altitude hypoxia exerts severe physiological stress on the human body, including embryonic auditory organ development.

Conclusion

The results of the present study indicate that the mutation spectrum of Tibetan Chinese patients with hearing loss is significantly different from that seen in patients of Han ethnicity. The incidence of inner ear malformation in the Tibetan Chinese population is almost as high as that in Chinese Han patients, but the types of malformation vary greatly in the Tibetan population. The most common inner ear deformity, enlarged vestibular aqueduct (EVA), is rare in the Chinese Tibetan hearing-loss population. Hypoxia may be one of the causes for the development of inner ear deformity, but further studies are required to determine the genetic etiology of hearing loss in Tibetan patients.

Acknowledgments

We thank the professional editors from Textcheck for English check of our manuscript. For a certificate, please see: http://www.textcheck.com/certificate/1XyxQd.

Author Contributions

Conceived and designed the experiments: PD D. Huang D. Han. Performed the experiments: SH LZ GZ GW YS. Analyzed the data: YY XZ. Contributed reagents/materials/analysis tools: HW. Wrote the paper: YY.

References

  1. 1. Cohen MM, Gorlin RJ (1995) Epidemiology, etiology and genetic patterns. In: Gorlin RJ, Toriello HV, Cohen MM, editors. Hereditary hearing loss and its snydromes. pp. 9–21.MM CohenRJ Gorlin1995Epidemiology, etiology and genetic patterns.RJ GorlinHV TorielloMM CohenHereditary hearing loss and its snydromes921Oxford University Press, Oxford. Oxford University Press, Oxford.
  2. 2. Hereditary Hearing Loss website. Hereditary Hearing Loss website.Available: http://hereditaryhearingloss.org/main.aspx?c=.HHH&n=86162 Accessed 2011 Dec 3. Available: http://hereditaryhearingloss.org/main.aspx?c=.HHH&n=86162 Accessed 2011 Dec 3.
  3. 3. Han DY (2010) Strengthen the research on prevention and treatment of sensorineural hearing loss in China. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 45(4): 265–268.DY Han2010Strengthen the research on prevention and treatment of sensorineural hearing loss in China.Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi454265268
  4. 4. Yuan Y, You Y, Huang D, Cui J, Wang Y, et al. (2009) Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China. J Transl Med 7: 79(1–12).Y. YuanY. YouD. HuangJ. CuiY. Wang2009Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China.J Transl Med779(112)
  5. 5. Estivill X, Fortina P, Surrey S, Rabionet R, Melchionda S, et al. (1998) Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet 351: 394–398.X. EstivillP. FortinaS. SurreyR. RabionetS. Melchionda1998Connexin-26 mutations in sporadic and inherited sensorineural deafness.Lancet351394398
  6. 6. Lench N, Houseman M, Newton V, Van Camp G, Mueller R (1998) Connexin-26 mutations in sporadic non-syndromal sensorineural deafness. Lancet 351: 415.N. LenchM. HousemanV. NewtonG. Van CampR. Mueller1998Connexin-26 mutations in sporadic non-syndromal sensorineural deafness.Lancet351415
  7. 7. Morell RJ, Kim HJ, Hood LJ, Goforth L, Friderici K, et al. (1998) Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med 339: 1500–1505.RJ MorellHJ KimLJ HoodL. GoforthK. Friderici1998Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness.N Engl J Med33915001505
  8. 8. Park HJ, Hahn SH, Chun YM, Park K, Kim HN (2000) Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope 110: 1535–1538.HJ ParkSH HahnYM ChunK. ParkHN Kim2000Connexin26 mutations associated with nonsyndromic hearing loss.Laryngoscope11015351538
  9. 9. Rabionet R, Zelante L, Lopez-Bigas N, D'Agruma L, Melchionda S, et al. (2000) Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet 106: 40–44.R. RabionetL. ZelanteN. Lopez-BigasL. D'AgrumaS. Melchionda2000Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene.Hum Genet1064044
  10. 10. Wilcox SA, Saunders K, Osborn AH, Arnold A, Wunderlich J, et al. (2000) High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet 106: 399–405.SA WilcoxK. SaundersAH OsbornA. ArnoldJ. Wunderlich2000High frequency hearing loss correlated with mutations in the GJB2 gene.Hum Genet106399405
  11. 11. Gabriel H, Kupsch P, Sudendey J, Winterhager E, Jahnke K, et al. (2001) Mutations in the connexin26/GJB2 gene are the most common event in non-syndromic hearing loss among the German population. Hum Mutat 17: 521–522.H. GabrielP. KupschJ. SudendeyE. WinterhagerK. Jahnke2001Mutations in the connexin26/GJB2 gene are the most common event in non-syndromic hearing loss among the German population.Hum Mutat17521522
  12. 12. Ohtsuka A, Yuge I, Kimura S, Namba A, Abe S, et al. (2003) GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet 112: 329–333.A. OhtsukaI. YugeS. KimuraA. NambaS. Abe2003GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation.Hum Genet112329333
  13. 13. Dai P, Yu F, Han B, Wang G, Li Q, et al. (2009) GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment. J Transl Med 7: 26(1–12).P. DaiF. YuB. HanG. WangQ. Li2009GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment.J Transl Med726(1–12)
  14. 14. Everett LA, Morsli H, Wu DK, Green ED (1999) Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear. Proc Natl Acad Sci USA 96: 9727–9732.LA EverettH. MorsliDK WuED Green1999Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear.Proc Natl Acad Sci USA9697279732
  15. 15. Royaux IE, Suzuki K, Mori A, Katoh R, Everett LA, et al. (2000) Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells. Endocrinology 141: 839–845.IE RoyauxK. SuzukiA. MoriR. KatohLA Everett2000Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells.Endocrinology141839845
  16. 16. Fischel-Ghodsian N (1998) Mitochondrial genetics and hearing loss: the missing link between genotype and phenotype. Proc Soc Exp Biol Med 218: 1–6.N. Fischel-Ghodsian1998Mitochondrial genetics and hearing loss: the missing link between genotype and phenotype.Proc Soc Exp Biol Med21816
  17. 17. Hutchin TP, Cortopassi GA (2000) Mitochondrial defects and hearing loss. Cell Mol Life Sci 57: 1927–1937.TP HutchinGA Cortopassi2000Mitochondrial defects and hearing loss.Cell Mol Life Sci5719271937
  18. 18. Zhao H, Li R, Wang Q, Yan Q, Deng JH, et al. (2004) Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet 74: 139–152.H. ZhaoR. LiQ. WangQ. YanJH Deng2004Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet74139152
  19. 19. Beall CM (2007) Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci U S A 104: suppl. 18655–8660.CM Beall2007Two routes to functional adaptation: Tibetan and Andean high-altitude natives.Proc Natl Acad Sci U S A104suppl. 186558660
  20. 20. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, et al. (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329(5987): 72–75.TS SimonsonY. YangCD HuffH. YunG. Qin2010Genetic evidence for high-altitude adaptation in Tibet.Science32959877275
  21. 21. Hwa HL, Ko TM, Hsu CJ, Huang CH, Chiang YL, et al. (2003) Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genet Med 5: 161–165.HL HwaTM KoCJ HsuCH HuangYL Chiang2003Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness.Genet Med5161165
  22. 22. Bonyadi M, Esmaeili M, Abhari M, Lotfi A (2009) Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients. Genet Test Mol Biomarkers 13(5): 689–692.M. BonyadiM. EsmaeiliM. AbhariA. Lotfi2009Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients.Genet Test Mol Biomarkers135689692
  23. 23. Tsukada K, Nishio S, Usami S (2010) A large cohort study of GJB2 mutations in Japanese hearing loss patients. Clin Genet 78(5): 464–470.K. TsukadaS. NishioS. Usami2010A large cohort study of GJB2 mutations in Japanese hearing loss patients.Clin Genet785464470
  24. 24. Mahdieh N, Rabbani B, Shirkavand A, Bagherian H, Movahed ZS, et al. (2011) Impact of Consanguineous Marriages in GJB2-Related Hearing Loss in the Iranian Population: A Report of a Novel Variant. Genet Test Mol Biomarkers 15(7–8): 489–493.N. MahdiehB. RabbaniA. ShirkavandH. BagherianZS Movahed2011Impact of Consanguineous Marriages in GJB2-Related Hearing Loss in the Iranian Population: A Report of a Novel Variant.Genet Test Mol Biomarkers157–8489493
  25. 25. Han SH, Park HJ, Kang EJ, Ryu JS, Lee A, et al. (2008) Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet 53(11–12): 1022–1028.SH HanHJ ParkEJ KangJS RyuA. Lee2008Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population.J Hum Genet5311–1210221028
  26. 26. Abidi O, Boulouiz R, Nahili H, Bakhouch K, Wakrim L, et al. (2008) Carrier frequencies of mutations/polymorphisms in the connexin 26 gene (GJB2) in the Moroccan population. Genet Test 12(4): 569–574.O. AbidiR. BoulouizH. NahiliK. BakhouchL. Wakrim2008Carrier frequencies of mutations/polymorphisms in the connexin 26 gene (GJB2) in the Moroccan population.Genet Test124569574
  27. 27. Ruszymah BH, Wahida IF, Zakinah Y, Zahari Z, Norazlinda MD, et al. (2005) Congenital deafness: high prevalence of a V37I mutation in the GJB2 gene among deaf school children in Alor Setar. Med J Malaysia 60(3): 269–274.BH RuszymahIF WahidaY. ZakinahZ. ZahariMD Norazlinda2005Congenital deafness: high prevalence of a V37I mutation in the GJB2 gene among deaf school children in Alor Setar.Med J Malaysia603269274
  28. 28. Zlotogora J, Carasquillo M, Barges S, Shalev SA, Hujerat Y, et al. (2006) High incidence of deafness from three frequent connexin 26 mutations in an isolated community. Genet Test 10(1): 40–43.J. ZlotogoraM. CarasquilloS. BargesSA ShalevY. Hujerat2006High incidence of deafness from three frequent connexin 26 mutations in an isolated community.Genet Test1014043
  29. 29. Dahl HH, Tobin SE, Poulakis Z, Rickards FW, Xu X, et al. (2006) The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. J Med Genet 43(11): 850–855.HH DahlSE TobinZ. PoulakisFW RickardsX. Xu2006The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children.J Med Genet4311850855
  30. 30. Gualandi E, Ravani A, Berto A, Burdo S, Trevisi P, et al. (2004) Occurrence of del(GIB6-D13S1830) mutation in Italian non-syndromic hearing loss patients carrying a single GJB2 mutated allele. Acta Otolaryngol Suppl 55229–34.E. GualandiA. RavaniA. BertoS. BurdoP. Trevisi2004Occurrence of del(GIB6-D13S1830) mutation in Italian non-syndromic hearing loss patients carrying a single GJB2 mutated allele.Acta OtolaryngolSuppl 5522934
  31. 31. Samanich J, Lowes C, Burk R, Shanske S, Lu J, et al. (2007) Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. Am J Med Genet A143A(8): 830–838.J. SamanichC. LowesR. BurkS. ShanskeJ. Lu2007Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment.Am J Med GenetA143A8830838
  32. 32. Shi GZ, Gong LX, Xu XH, Nie WY, Lin Q, et al. (2004) GJB2 gene mutations in newborns with non-syndromic hearing impairment in Northern China. Hear Res 197(1–2): 19–23.GZ ShiLX GongXH XuWY NieQ. Lin2004GJB2 gene mutations in newborns with non-syndromic hearing impairment in Northern China.Hear Res1971–21923
  33. 33. Wattanasirichaigoon D, Limwongse C, Jariengprasert C, Yenchitsomanus PT, Tocharoenthanaphol C, et al. (2004) High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals. Clin Genet 66(5): 452–460.D. WattanasirichaigoonC. LimwongseC. JariengprasertPT YenchitsomanusC. Tocharoenthanaphol2004High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals.Clin Genet665452460
  34. 34. Roux AF, Pallares-Ruiz N, Vielle A, Faugère V, Templin C, et al. (2004) Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet 5: 5.AF RouxN. Pallares-RuizA. VielleV. FaugèreC. Templin2004Molecular epidemiology of DFNB1 deafness in France.BMC Med Genet55
  35. 35. Yong AM, Goh SS, Zhao Y, Eng PH, Koh LK, et al. (2001) Two Chinese families with Pendred's syndrome–radiological imaging of the ear and molecular analysis of the pendrin gene. J Clin Endocrinol Metab 86(8): 3907–3911.AM YongSS GohY. ZhaoPH EngLK Koh2001Two Chinese families with Pendred's syndrome–radiological imaging of the ear and molecular analysis of the pendrin gene.J Clin Endocrinol Metab86839073911
  36. 36. Office of the 2nd nationwide survey of the disabled Chinese population (2007) Handbook of major data on the 2nd nationwide survey of the disabled Chinese population. Beijing: HuaXia publishing company. Office of the 2nd nationwide survey of the disabled Chinese population2007Handbook of major data on the 2nd nationwide survey of the disabled Chinese populationBeijingHuaXia publishing company238
  37. 37. Snoeckx RL, Huygen PL, Feldmann D, Marlin S, Denoyelle F, et al. (2005) GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet 77: 945–957.RL SnoeckxPL HuygenD. FeldmannS. MarlinF. Denoyelle2005GJB2 mutations and degree of hearing loss: a multicenter study.Am J Hum Genet77945957
  38. 38. Wu BL, Lindeman N, Lip V, Adams A, Amato RS, et al. (2002) Effectiveness of sequencing connexin 26(GJB2) in familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med 4: 279–288.BL WuN. LindemanV. LipA. AdamsRS Amato2002Effectiveness of sequencing connexin 26(GJB2) in familial or sporadic childhood deafness referred for molecular diagnostic testing.Genet Med4279288
  39. 39. Stankovic KM, Hennessey AM, Herrmann B, Mankarious LA (2010) Cochlear implantation in children with congenital X-linked deafness due to novel mutations in POU3F4 gene. Ann Otol Rhinol Laryngol 119(12): 815–822.KM StankovicAM HennesseyB. HerrmannLA Mankarious2010Cochlear implantation in children with congenital X-linked deafness due to novel mutations in POU3F4 gene.Ann Otol Rhinol Laryngol11912815822
  40. 40. Li J, Cheng J, Lu Y, Lu Y, Chen A, et al. (2010) Identification of a novel mutation in POU3F4 for prenatal diagnosis in a Chinese family with X-linked nonsyndromic hearing loss. J Genet Genomics 37(12): 787–793.J. LiJ. ChengY. LuY. LuA. Chen2010Identification of a novel mutation in POU3F4 for prenatal diagnosis in a Chinese family with X-linked nonsyndromic hearing loss.J Genet Genomics3712787793
  41. 41. Han B, Cheng J, Yang SZ, Cao JY, Shen WD, et al. (2009) Phenotype and genotype analysis of a Chinese family with prelingual X-linked hereditary hearing impairment. Chin Med J (Engl) 122(7): 830–833.B. HanJ. ChengSZ YangJY CaoWD Shen2009Phenotype and genotype analysis of a Chinese family with prelingual X-linked hereditary hearing impairment.Chin Med J (Engl)1227830833
  42. 42. Lee HK, Lee SH, Lee KY, Lim EJ, Choi SY, et al. (2009) Novel POU3F4 mutations and clinical features of DFN3 patients with cochlear implants. Clin Genet 75(6): 572–575.HK LeeSH LeeKY LeeEJ LimSY Choi2009Novel POU3F4 mutations and clinical features of DFN3 patients with cochlear implants.Clin Genet756572575
  43. 43. Minowa O, Ikeda K, Sugitani Y, Oshima T, Nakai S, et al. (1999) Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness. Science 285: 1408–1411.O. MinowaK. IkedaY. SugitaniT. OshimaS. Nakai1999Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness.Science28514081411
  44. 44. Phippard D, Heydemann A, Lechner M, Lu L, Lee D, et al. (1998) Changes in the subcellular localization of the Brn4 gene product precede mesenchymal remodeling of the otic capsule. Hear Res 120: 77–85.D. PhippardA. HeydemannM. LechnerL. LuD. Lee1998Changes in the subcellular localization of the Brn4 gene product precede mesenchymal remodeling of the otic capsule.Hear Res1207785
  45. 45. Burton Q, Cole LK, Mulheisen M, Chang W, Wu DK (2004) The role of Pax2 in mouse inner ear development. Dev Biol 272: 161–175.Q. BurtonLK ColeM. MulheisenW. ChangDK Wu2004The role of Pax2 in mouse inner ear development.Dev Biol272161175
  46. 46. Ozaki H, Nakamura K, Funahashi J, Ikeda K, Yamada G, et al. (2004) Six1 controls patterning of the mouse otic vesicle. Development 131: 551–562.H. OzakiK. NakamuraJ. FunahashiK. IkedaG. Yamada2004Six1 controls patterning of the mouse otic vesicle.Development131551562
  47. 47. Xu PX, Adams J, Peters H, Brown MC, Heaney S, et al. (1999) Eya1 - deficient mice lack ears and kidneys and show abnormal apoptosis of organ pripordia. Nat Genet 23: 113–117.PX XuJ. AdamsH. PetersMC BrownS. Heaney1999Eya1 - deficient mice lack ears and kidneys and show abnormal apoptosis of organ pripordia.Nat Genet23113117
  48. 48. Merlo GR, Paleari L, Mantero S, Zerega B, Adamska M, et al. (2002) The Dlx5 homebox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP - mediated pathway[J]. Dev Bilo 248: 157–169.GR MerloL. PaleariS. ManteroB. ZeregaM. Adamska2002The Dlx5 homebox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP - mediated pathway[J].Dev Bilo248157169
  49. 49. Wang W, Chan EK, Baron S, Van de Water T, Lufkin T (2001) Hmx2 homeobox gene control of murine vestibular morphogenesis. Development 128(24): 5017–5029.W. WangEK ChanS. BaronT. Van de WaterT. Lufkin2001Hmx2 homeobox gene control of murine vestibular morphogenesis.Development1282450175029
  50. 50. Karis A, Pata I, van Doorninck JH, Grosveld F, de Zeeuw CI, et al. (2001) Transcription factor GATA- 3 alters pathway selection of oliv ochochlear neurons and affects morphogenesis of the ear. J Comp Neurol 429: 615–630.A. KarisI. PataJH van DoorninckF. GrosveldCI de Zeeuw2001Transcription factor GATA- 3 alters pathway selection of oliv ochochlear neurons and affects morphogenesis of the ear.J Comp Neurol429615630
  51. 51. Romand R, Niederreither K, Abu-Abed S, Petkovich M, Fraulob V, et al. (2004) Complementary expression patterns of retinoid acid - synthesizing and – metabolizing enzymes in pre - natal mouse inner ear structures. Gene Expr Patterns 4: 123–133.R. RomandK. NiederreitherS. Abu-AbedM. PetkovichV. Fraulob2004Complementary expression patterns of retinoid acid - synthesizing and – metabolizing enzymes in pre - natal mouse inner ear structures.Gene Expr Patterns4123133
  52. 52. Morsli H, Tuorto F, Choo D, Postiglione MP, Simeone A, et al. (2005) Otx1 and Otx2 activities are required for the normal development of the mouse inner ear. Development 126: 2235–2343.H. MorsliF. TuortoD. ChooMP PostiglioneA. Simeone2005Otx1 and Otx2 activities are required for the normal development of the mouse inner ear.Development12622352343
  53. 53. Camarero G, Villar MA, Contreras J, Fernández-Moreno C, Pichel JG, et al. (2002) Cochlear abnormalities in insulin-like growth factor-1 mouse mutants. Hear Res 170: 2–11.G. CamareroMA VillarJ. ContrerasC. Fernández-MorenoJG Pichel2002Cochlear abnormalities in insulin-like growth factor-1 mouse mutants.Hear Res170211
  54. 54. Moraes F, Nóvoa A, Jerome-Majewska LA, Papaioannou VE, Mallo M (2005) Tbx1 is required for proper neural crest migration and to stabilize spatial patterns during middle and inner ear development. Mech Dev 122: 199–212.F. MoraesA. NóvoaLA Jerome-MajewskaVE PapaioannouM. Mallo2005Tbx1 is required for proper neural crest migration and to stabilize spatial patterns during middle and inner ear development.Mech Dev122199212
  55. 55. Niermeyer S, Zamdio S, Moore LG (2001) The People. In: HTaS RB, editor. High Altitude: An exploration of Human Adaptation. New York: Marcel Dekker, Inc. S. NiermeyerS. ZamdioLG Moore2001The People.RB HTaSHigh Altitude: An exploration of Human AdaptationNew YorkMarcel Dekker, Inc
  56. 56. Wang J, Wang ZN, Li SZ, Wang LJ, Chen ZD, et al. (2002) Examination on congenital heart disease for 6500 students. Tibet's Science and Technology 1: 12–14.J. WangZN WangSZ LiLJ WangZD Chen2002Examination on congenital heart disease for 6500 students.Tibet's Science and Technology11214
  57. 57. Liu RC, Wu TY, Ge RL (1982) Survey on congenital heart disease in Qinghai Plateau. Chin J Cardiol l 0: 241–242.RC LiuTY WuRL Ge1982Survey on congenital heart disease in Qinghai Plateau.Chin J Cardiol l0241242
  58. 58. Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, et al. (1998) Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106: 385–400.CM BeallGM BrittenhamKP StrohlJ. BlangeroS. Williams-Blangero1998Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara.Am J Phys Anthropol106385400
  59. 59. Beall CM, Blangero J, Williams-Blangero S, Goldstein MC (1994) Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders. Am J Phys Anthropol 95: 271–276.CM BeallJ. BlangeroS. Williams-BlangeroMC Goldstein1994Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders.Am J Phys Anthropol95271276
  60. 60. Beall CM, Strohl KP, Blangero J, Williams-Blangero S, Decker MJ, et al. (1997) Quantitative genetic analysis of arterial oxygen saturation in Tibetan highlanders. Hum Biol 69: 597–604.CM BeallKP StrohlJ. BlangeroS. Williams-BlangeroMJ Decker1997Quantitative genetic analysis of arterial oxygen saturation in Tibetan highlanders.Hum Biol69597604