Genetic basis of Y-linked hearing impairment

Abstract

A single Mendelian trait has been mapped to the human Y chromosome: Y-linked hearing impairment. The molecular basis of this disorder is unknown. Here, we report the detailed characterization of the DFNY1 Y chromosome and its comparison with a closely related Y chromosome from an unaffected branch of the family. The DFNY1 chromosome carries a complex rearrangement, including duplication of several noncontiguous segments of the Y chromosome and insertion of ∼160 kb of DNA from chromosome 1, in the pericentric region of Yp. This segment of chromosome 1 is derived entirely from within a known hearing impairment locus, DFNA49. We suggest that a third copy of one or more genes from the shared segment of chromosome 1 might be responsible for the hearing-loss phenotype.

Figure 1

The DFNY1 Pedigree Males, squares; females, circles; diagonal line, deceased. Filled symbols indicate hearing impairment (including from family records); question marks indicate two individuals whose hearing phenotype is unknown; and asterisks indicate individuals who are on the affected branch but who were below the age of onset of symptoms at the time of examination. Arrows indicate the two individuals whose Y chromosomes were sequenced. The structural rearrangement occurred during one of the four meioses marked by red stars. Spouses are omitted in generations VII-IX and in generation VI on the unaffected branch.

Figure 2

Characterization of the Structural Rearrangement Carried by the DFNY1 Y Chromosome (A) Relative read depth (affected/unaffected) in 10 kb bins mapped to the Y chromosome reference sequence between 9.3 and 10.1 Mb. Note the assembly gaps at each end of this region. (B) CGH log2 ratio (affected/unaffected) for the same region. (C) Fiber-FISH of the three BAC clones indicated to the unaffected Y chromosome, showing that it carries the reference structure in this region. Both 334D2 and 108I14 detect tandem arrays larger than the size of the BAC clone. (D) Fiber-FISH of the same BAC clones to the affected Y chromosome. This chromosome carries an insertion that interrupts the 182H20-hybridizing region and contains partial duplications of both 334D2- and 108I14-hybridizing sequences. (E) Absolute read depth of unaffected and affected Y chromosome reads to the 160.15–160.35 Mb region of the chromosome 1 reference sequence. (F) CGH log2 ratio (affected/unaffected) for the same chromosome 1 region. (G) Metaphase FISH of the chromosome 1 BAC clone 179G5 on the unaffected Y chromosome (yellow). Hybridization is seen only at the reference location on chromosome 1. (H) Metaphase FISH of the same chromosome 1 probe on the affected Y chromosome (yellow). Hybridization is seen at an additional locus on the Y chromosome. (I) Fiber-FISH of the two Y BAC clones indicated plus the chromosome 1 clones 574F21, 179G5 and 1365F20 to the unaffected Y chromosome. No chromosome 1 signal is detected on the Y. (J) Fiber-FISH of the same clones to the unaffected Y chromosome. The chromosome 1 clones detect a signal on the Y between the partial 182H20 signal and the 108I14 signal. Genome coordinates refer to GRCh37/hg19.

Figure 3

Structure and Gene Content of the Unaffected and Affected Y Chromosomes (A) The structure of the unaffected (VII-24 in Figure 1) Y chromosome. Grey and black: errors and gaps, respectively, in the GRCH37 assembly. Blue: region matching the reference sequence at the level of resolution used. Shown below are part of the TSPY1 array (blue arrowheads) and the location of BAC clone signals identified in Figure 2. (B) Structure of the affected (VIII-2 in Figure 1) Y chromosome. This chromosome contains a segment that is not in the unaffected chromosome; this segment is derived from duplications of sequences from both chromosome 1 (yellow) and the Y chromosome (blue). Again, the gene content and BAC signals are shown below. The arrowheads above indicate the orientation of the duplicated segments relative to the reference sequence. (C) Detailed view of the two chromosome 1-Y junctions studied at the sequence level (Figures S2 and S3), showing the difference between the simple structure of junction 1 and the complex structure of junction 2.